Bicyclic heterocyclic amide derivative

ABSTRACT

The present invention provides a bicyclic heterocyclic amide derivative of formula (1) wherein ring Q 1  is optionally-substituted C 6-10  aryl group, etc.; R 1  and R 2  are independently hydrogen atom, etc.; W 1  is optionally-substituted C 1-4  alkylene group; W 2  is —NR 3a C(O)—, etc. wherein R 3a  is hydrogen atom or C 1-6  alkyl group; Cy 1  is the following group of formula (11), etc.; ring Q 2  is optionally-substituted benzene ring, etc.; n and m are independently 0, 1 or 2, provided that n and m are not simultaneously 0; X is NR 5 , etc.; R 5  is hydrogen atom, etc.; p is 1, 2, 3, 4 or 5; R 4  is, independently when two or more exist, hydrogen atom, etc.; and a pharmacologically acceptable salt thereof, which have a potent inhibitory effect on the sphere-forming ability of cancer cells and are useful as an orally-available anti-tumor agent.

TECHNICAL FIELD

The present invention relates to a pharmaceutically-useful bicyclicheterocyclic amide derivative including a pharmaceutically acceptablesalt thereof, and an anti-tumor agent comprising it as an activeingredient.

BACKGROUND ART

Conventional cancer treatments are sometimes not expected to bring inmeaningful survival effects even if they can induce the regression oftumors, because of the persistent proliferation of malignant tumors, themetastasis or recurrence of cancer, and the resistance to an anti-tumoragent. These days, it has been suggested that cancer stem cell(hereinafter referred to as “CSC”, as necessary) is one of the reasonsof the failure, which is closely involved in the factors such as thepersistent proliferation of malignant tumor. CSCs have been identifiedin almost all types of major cancers in human such as breast cancer,colon cancer, lung cancer, and hematological malignancy (Non-PatentDocument 1). Also, CSCs can be greatly different in the biologicalfeature from standard cancer cells which differentiate from CSCs, andthus the development of an anti-tumor agent whose target is CSCs isexpected to lead to a new strategy for cancer treatments (Non-PatentDocument 2).

One of the features in CSCs is the self-renewal ability (Non-PatentDocument 3). Reliable methods established for measuring the self-renewalability of cells include, for example, a method for measuring thesphere-forming ability of cancer cells in non-adherent condition in theabsence of serum (Non-Patent Document 4).

Non-Patent Document 5 discloses that PF-03084014 having anN-imidazolylamide skeleton can inhibit CSCs to exhibit an anti-cancereffect. However, Non-Patent Document 5 does not disclose the compound offormula (1) of the present invention.

PRIOR ART DOCUMENTS Non-Patent Documents

Non-Patent Document 1: Boman et al., Journal of Clinical Oncology26(17): 2795-2799. 2008

Non-Patent Document 2: Lobo et al., Annu Rev Cell Dev Biol 23: 675-99.2007

Non-Patent Document 3: Al-Hajj et al., Oncogene 23(43): 7274-82. 2004

Non-Patent Document 4: Ponti et al., Cancer Res 65(13): 5506-11. 2005

Non-Patent Document 5: Zhang et al., Stem Cells Translational Medicine2: 233-242. 2013

SUMMARY OF INVENTION Problem to be Solved by the Invention

An object of the present invention is to provide a novel anti-tumoragent whose target is CSCs which are thought to be closely involved inthe persistent proliferation of malignant tumor, the metastasis orrecurrence of cancer, and the resistance to an anti-tumor agent.

Means for Solving the Problems

The present inventors have extensively studied to reach the aboveobject, and then have found that a compound of the following formula (1)or a pharmaceutically acceptable salt thereof (hereinafter referred toas “the present compound”, as necessary) has a potent inhibitory effecton the sphere-forming ability of cancer cells and is highly useful as anovel anti-tumor agent. Based upon the new findings, the presentinvention has been completed.

The present invention provides inventions described below.

-   [1] A compound of formula (1):

or a pharmaceutically acceptable salt thereof, wherein ring Q¹ isoptionally-substituted C₆₋₁₀ aryl group, optionally-substituted C₃₋₁₀cycloalkyl group, or optionally-substituted 5- to 10-membered heteroarylgroup;

R¹ and R² are independently hydrogen atom, halogen atom, or C₁₋₆ alkylgroup which may be optionally substituted with the same or different 1to 3 halogen atoms;

W¹ is optionally-substituted C₁₋₄ alkylene group;

W²-Cy¹ is —NR^(3a)C(O)-Cy¹, —NR^(3a)C(O)O-Cy¹, —NR^(3a)C(O)OCH₂-Cy¹,—NR^(3a)C(O)NR^(3b)-Cy¹, —NR^(3a)C(O)NR^(3b)CH₂-Cy¹,—NR^(3a)C(O)CH₂O-Cy¹, —NR^(3a)C(O)CH₂-Cy¹, —NR^(3a)C(O)CH₂CH₂-Cy¹,—C(O)NR^(3a)-Cy¹, —C(O)NR^(3a)CH₂—C(O)NR^(3a)CH₂CH₂-Cy¹, or—NR^(3a)C(O)—CR^(3c)═CR³-Cy¹ wherein R^(3a) and R^(3b) are independentlyhydrogen atom or C₁₋₆ alkyl group; and R^(3c) and R^(3d) areindependently hydrogen atom, fluorine atom, or C₁₋₆ alkyl group; and

Cy¹ is a group of the following formula (11), (12), (13), (14), (15), or(16):

wherein ring Q² is optionally-substituted benzene ring,optionally-substituted pyridine ring, optionally-substituted pyrimidinering, optionally-substituted pyridazine ring, or optionally-substitutedpyrazine ring;

ring Q³ is optionally-substituted 5-membered heteroaryl ring;

n and m are independently 0, 1 or 2, provided that n and m are notsimultaneously 0;

X and Z are independently NR⁵, —NR^(3e)C(O)—, —C(O)NR^(3e)—, or Owherein R⁵ is hydrogen atom, C₁₋₆ alkyl group which may be optionallysubstituted with the same or different 1 to 3 halogen atoms, or C₁₋₆alkylcarbonyl; and R^(3e) is hydrogen atom or C₁₋₆ alkyl group;

p is 1, 2, 3, 4 or 5; and

R⁴ is, independently when two or more exist, hydrogen atom, halogenatom, hydroxy, oxo, C₁₋₆ alkyl group which may be optionally substitutedwith the same or different 1 to 3 halogen atoms, or C₁₋₆ alkoxy groupwhich may be optionally substituted with the same or different 1 to 3halogen atoms; or

when two R⁴ are attached to the same carbon atom or the adjacent carbonatoms on the ring, they may be combined with the carbon atom(s) to form

-   (1) 5- to 8-membered saturated or partially-unsaturated carbocyclic    ring which may be optionally substituted with the same or different    1 to 4 groups selected from the group consisting of halogen atom,    hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, or-   (2) 5- to 8-membered saturated or partially-unsaturated heterocyclic    ring which may be optionally substituted with the same or different    1 to 4 groups selected from the group consisting of halogen atom,    hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy.-   [2] A compound of formula (1):

or a pharmaceutically acceptable salt thereof, wherein ring Q¹ isoptionally-substituted C₆₋₁₀ aryl group, optionally-substituted C₃₋₁₀cycloalkyl group, or optionally-substituted 5- to 10-membered heteroarylgroup;

R¹ and R² are independently hydrogen atom, halogen atom, or C₁₋₆ alkylgroup which may be optionally substituted with the same or different 1to 3 halogen atoms;

W¹ is optionally-substituted C₁₋₄ alkylene group;

W²-Cy1 is —NR^(3a)C(O)-Cy¹, —NR^(3a)C(O)O-Cy¹, —NR^(3a)C(O)OCH₂-Cy¹,—NR^(3a)C(O)NR^(3b)-Cy¹, —NR^(3a)C(O)NR^(3b)CH₂-Cy¹,—NR^(3a)C(O)CH₂O-Cy¹, —NR^(3a)C(O)CH₂-Cy¹, —NR^(3a)C(O)CH₂CH₂-Cy¹,—C(O)NR^(3a)-Cy¹, —C(O)NR^(3a)CH₂-Cy¹, or —C(O)NR^(3a)CH₂CH₂-Cy whereinR^(3a) and R^(3b) are independently hydrogen atom or C₁₋₆ alkyl group;and

Cy¹ is a group of the following formula (11), (12), or (13):

wherein ring Q² is optionally-substituted benzene ring,optionally-substituted pyridine ring, optionally-substituted pyrimidinering, optionally-substituted pyridazine ring, or optionally-substitutedpyrazine ring;

ring Q³ is optionally-substituted 5-membered heteroaryl ring;

n and m are independently 0, 1 or 2, provided that n and m are notsimultaneously 0;

X is NR⁵ or O wherein R⁵ is hydrogen atom or C₁₋₆ alkyl group which maybe optionally substituted with the same or different 1 to 3 halogenatoms;

p is 1, 2, 3, 4 or 5; and

R⁴ is, independently when two or more exist, hydrogen atom, halogenatom, or C₁₋₆ alkyl group which may be optionally substituted with thesame or different 1 to 3 halogen atoms.

-   [3] The compound according to [1] or [2] or a pharmaceutically    acceptable salt thereof, wherein ring Q¹ is-   (1) C₆₋₁₀ aryl group which may be optionally substituted with the    same or different 1 to 5 groups selected from the group consisting    of:

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same ordifferent 1 to 3 groups selected from the group consisting of halogenatom, hydroxy, and C₁₋₆ alkoxy,

(c) C₁₋₆ alkoxy which may be optionally substituted with the same ordifferent 1 to 3 groups selected from the group consisting of halogenatom, hydroxy, and C₁₋₆ alkoxy,

(d) cyano,

(e) C₆₋₁₀ aryl which may be optionally substituted with the same ordifferent 1 to 4 groups selected from the group consisting of halogenatom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(f) 5- or 6-membered heteroaryl which may be optionally substituted withthe same or different 1 to 4 groups selected from the group consistingof halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(g) C₆₋₁₀ aryloxy which may be optionally substituted with the same ordifferent 1 to 4 groups selected from the group consisting of halogenatom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(h) hydroxy,

(i) amino which may be optionally substituted with the same or different1 to 2 C₁₋₆ alkyl groups,

(j) aminocarbonyl wherein the amino moiety thereof may be optionallysubstituted with the same or different 1 to 2 C₁₋₆ alkyl groups,

(k) C₁₋₆ alkoxy-carbonyl wherein the alkoxy moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(l) C₁₋₆ alkyl-carbonyl wherein the alkyl moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(m) C₁₋₆ alkylsulfonyl wherein the alkyl moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(n) C₁₋₆ alkyl-carbonylamino wherein the alkyl moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(o) C₁₋₆ alkylsulfonylamino wherein the alkyl moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(p) C₁₋₆ alkoxy-carbonylamino wherein the alkoxy moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(q) alkyl-carbonyloxy wherein the alkyl moiety thereof may be optionallysubstituted with the same or different 1 to 3 groups selected from thegroup consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(r) aminosulfonyl wherein the amino moiety thereof may be optionallysubstituted with the same or different 1 to 2 C₁₋₆ alkyl groups, and

(s) C₃₋₁₀ cycloalkyl which may be optionally substituted with the sameor different 1 to 4 groups selected from the group consisting of halogenatom, hydroxy, and C₁₋₆ alkoxy,

-   (2) C₃₋₁₀ cycloalkyl group which may be optionally substituted with    the same or different 1 to 5 groups selected from the group    consisting of (a) to (s) defined in the above (1), or-   (3) 5- to 10-membered heteroaryl group which may be optionally    substituted with the same or different 1 to 5 groups selected from    the group consisting of (a) to (s) defined in the above (1);

W¹ is C₁₋₄ alkylene group which may be optionally substituted with thesame or different 1 to 4 groups selected from the group consisting ofhalogen atom, hydroxy, and C₁₋₆ alkoxy;

ring Q² is benzene ring, pyridine ring, pyrimidine ring, pyridazinering, or pyrazine ring wherein the benzene ring, pyridine ring,pyrimidine ring, pyridazine ring, and pyrazine ring may be optionallysubstituted with the same or different 1 to 3 groups selected from thegroup consisting of halogen atom; C₁₋₆ alkyl which may be optionallysubstituted with the same or different 1 to 4 groups selected from thegroup consisting of the same or different 1 to 3 halogen atoms, hydroxyand C₁₋₆ alkoxy; C₁₋₆ alkoxy which may be optionally substituted withthe same or different 1 to 3 halogen atoms; hydroxy; and cyano;

ring Q³ is 5-membered heteroaryl ring which may be optionallysubstituted with halogen atom or C₁₋₆ alkyl which may be optionallysubstituted with the same or different 1 to 4 groups selected from thegroup consisting of the same or different 1 to 3 halogen atoms, hydroxyand C₁₋₆ alkoxy.

-   [4] The compound according to any one of [1] to [3] or a    pharmaceutically acceptable salt thereof, wherein ring Q¹ is-   (1) phenyl group which may be optionally substituted with the same    or different 1 to 5 groups selected from the group consisting of:

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same ordifferent 1 to 3 groups selected from the group consisting of halogenatom, hydroxy and C₁₋₆ alkoxy,

(c) C₁₋₆ alkoxy which may be optionally substituted with the same ordifferent 1 to 3 groups selected from the group consisting of halogenatom, hydroxy and C₁₋₆ alkoxy,

(d) cyano,

(e) phenyl which may be optionally substituted with the same ordifferent 1 to 4 groups selected from the group consisting of halogenatom, C₁₋₆ alkyl and C₁₋₆ alkoxy,

(f) 5- or 6-membered heteroaryl which may be optionally substituted withthe same or different 1 to 4 groups selected from the group consistingof halogen atom, C₁₋₆ alkyl and C₁₋₆ alkoxy, and

(g) phenoxy which may be optionally substituted with the same ordifferent 1 to 4 groups selected from the group consisting of halogenatom, C₁₋₆ alkyl and C₁₋₆ alkoxy,

-   (2) C₃₋₇ cycloalkyl group which may be optionally substituted with 1    to 4 groups selected from the group consisting of (a) to (g) defined    in the above (1), or-   (3) pyridyl group which may be optionally substituted with 1 to 4    groups selected from the group consisting of (a) to (g) defined in    the above (1).-   [5] The compound according to any one of [1] to [4] or a    pharmaceutically acceptable salt thereof, wherein ring Q¹ is phenyl    group which may be optionally substituted with the same or different    1 to 5 groups selected from the group consisting of:

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same ordifferent 1 to 3 halogen atoms, and

(c) C₁₋₆ alkoxy which may be optionally substituted with the same ordifferent 1 to 3 halogen atoms.

-   [6] The compound according to any one of [1] to [5] or a    pharmaceutically acceptable salt thereof, wherein W¹ is methylene    group which may be optionally substituted with the same or different    1 to 2 halogen atoms or ethylene group which may be optionally    substituted with the same or different 1 to 4 halogen atoms.-   [7] The compound according to any one of [1] to [6] or a    pharmaceutically acceptable salt thereof, wherein W²-Cy¹ is    —NR^(3a)C(O)-Cy¹ or —C(O)NR^(3a)-Cy¹ wherein R^(3a)is hydrogen atom    or C₁₋₆ alkyl group.-   [8] The compound according to any one of [1] to [7] or a    pharmaceutically acceptable salt thereof, wherein W²-Cy¹ is    —NR^(3a)C(O)-Cy¹ wherein R^(3a) is hydrogen atom or C₁₋₆ alkyl    group.-   [9] The compound according to [1] represented by formula (1a):

or a pharmaceutically acceptable salt thereof, wherein ring Q^(1a) isphenyl group, pyridyl group, or cyclohexyl group;

q is 1, 2, 3, 4 or 5;

R¹¹ is, independently when two or more exist,

-   (1) hydrogen atom,-   (2) halogen atom,-   (3) C₁₋₆ alkyl group which may be optionally substituted with the    same or different 1 to 3 halogen atoms, or-   (4) C₁₋₆ alkoxy group which may be optionally substituted with the    same or different 1 to 3 halogen atoms;

R¹ and R² are independently hydrogen atom, halogen atom, or C₁₋₆ alkylgroup which may be optionally substituted with the same or different 1to 3 halogen atoms;

W^(1a) is methylene group which may be optionally substituted with thesame or different 1 to 2 halogen atoms or ethylene group which may beoptionally substituted with the same or different 1 to 4 halogen atoms;

W^(2a)-Cy² is —NR^(3a)C(O)-Cy² or —C(O)NR^(3a)-Cy² wherein R^(3a) ishydrogen atom or C₁₋₆ alkyl group; and

Cy² is a group of the following formula (21), (22), or (23):

wherein X¹ is N or CR¹²;

X² is N or CR¹³;

X³ is N or CR¹⁴;

X⁴ is N or CR¹⁵;

X⁵ is S, O or NH;

provided that X¹, X² and X³ are not simultaneously N;

R¹², R¹³, R¹⁴ and R¹⁵ are independently

-   (1) hydrogen atom,-   (2) halogen atom,-   (3) C₁₋₆ alkyl group which may be optionally substituted with the    same or different 1 to 3 halogen atoms, or-   (4) C₁₋₆ alkoxy group which may be optionally substituted with the    same or different 1 to 3 halogen atoms;

n and m are independently 0, 1 or 2, provided that n and m are notsimultaneously 0;

p is 1, 2, 3, 4 or 5; and

R⁴ is, independently when two or more exist, hydrogen atom, halogenatom, or C₁₋₆ alkyl group which may be optionally substituted with thesame or different 1 to 3 halogen atoms.

-   [10] The compound according to [9] or a pharmaceutically acceptable    salt thereof, wherein ring Q^(1a) is phenyl group.-   [11] The compound according to [9] or [10] or a pharmaceutically    acceptable salt thereof, wherein W^(2a)-Cy² is —NHC(O)-Cy².-   [12] The compound according to [9] or [10] or a pharmaceutically    acceptable salt thereof, wherein W^(2a)-Cy² is —C(O)NH-Cy².-   [13] The compound according to any one of [9] to [12] or a    pharmaceutically acceptable salt thereof, wherein Cy² is a group of    formula (21) or (23).-   [14] The compound according to any one of [9] to [12] or a    pharmaceutically acceptable salt thereof, wherein Cy² is a group of    formula (22); X⁴ is N or CH; and X⁵ is S.-   [15] The compound according to any one of [1] to [14] or a    pharmaceutically acceptable salt thereof, wherein R¹ and R² are    hydrogen atom.-   [16] The compound according to [1] represented by formula (1b):

or a pharmaceutically acceptable salt thereof, wherein is N or CR¹²;

X² is N or CR¹³;

X³ is N or CR¹⁴;

provided that X¹, X² and X³ are not simultaneously N;

W^(2b) is —NHC(O)— or —C(O)NH—;

R¹², R¹³, R¹⁴, R²¹, R²², R²³, R²⁴, and R²⁵ are independently

-   (1) hydrogen atom,-   (2) halogen atom,-   (3) C₁₋₆ alkyl group which may be optionally substituted with the    same or different 1 to 3 halogen atoms, or-   (4) C₁₋₆ alkoxy group which may be optionally substituted with the    same or different 1 to 3 halogen atoms;

n and m are independently 0, 1 or 2, provided that n and m are notsimultaneously 0;

p is 1, 2, 3, 4 or 5; and

R⁴ is, independently when two or more exist, hydrogen atom, halogenatom, or C₁₋₆ alkyl group which may be optionally substituted with thesame or different 1 to 3 halogen atoms.

-   [17] The compound according to [16] or a pharmaceutically acceptable    salt thereof, wherein R²² is halogen atom or C₁₋₆ alkyl group which    may be optionally substituted with the same or different 1 to 3    halogen atoms.-   [18] The compound according to [16] or a pharmaceutically acceptable    salt thereof, wherein R²² is halogen atom.-   [19] The compound according to any one of [16] to [18] or a    pharmaceutically acceptable salt thereof, wherein R²¹, R²³, R²⁴ and    R²⁵ are independently-   (1) hydrogen atom,-   (2) halogen atom, or-   (3) C₁₋₆ alkyl group which may be optionally substituted with the    same or different 1 to 3 halogen atoms.-   [20] The compound according to any one of [16] to [19] or a    pharmaceutically acceptable salt thereof wherein W^(2b) is —NRC(O)—.-   [21] The compound according to any one of [16] to [19] or a    pharmaceutically acceptable salt thereof, wherein W^(2b) is    —C(O)NH—.-   [22] The compound according to any one of [9] to [21] or a    pharmaceutically acceptable salt thereof, wherein only one of X¹, X²    and X³ is N.-   [23] The compound according to any one of [1] to [22] or a    pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen    atom.-   [24] The compound according to any one of [1] to [23] or a    pharmaceutically acceptable salt thereof, wherein n is 1 and m is 1;    or n is 2 and m is 0.-   [25] The compound according to any one of [1] to [24] or a    pharmaceutically acceptable salt thereof, wherein n is 1 and m is 1.-   [26] The compound according to [1] selected from the following    compounds or a pharmaceutically acceptable salt thereof:

N-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamide(Example 1),

N-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamide(Example 3),

N-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamide(Example 4),

8-fluoro-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 5),

N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 6),

N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxamide(Example 8),

N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxamide(Example 9),

N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide(Example 10),

N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide(Example 11),

N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 12),

N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 13),

N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 19),

1-(3,4-difluorobenzyl)-N-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-1H-imidazole-4-carboxamide(Example 35),

N-[1-(3,5-difluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 47),

N-[1-(3,4-difluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 48),

N-{1-[3-(trifluoromethoxy)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 49),

N-[1-(3-phenoxybenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide (Example 50),

N-[1-(4-chloro-3-fluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 51),

N-[1-(3-chloro-5-fluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 52),

N-{1-[4-fluoro-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 53),

N-{1-[4-chloro-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 54),

N-{1-[4-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 64),

N-[1-(4-chlorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 65),

N-{1-[3-chloro-5-(trifluoromethoxy)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 70),

N-[1-(3-phenoxybenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 89),

N-[1-(4-chloro-3-fluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 90),

N-[1-(3-chloro-5-fluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 91),

N-{1-[4-fluoro-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 92),

N-(1-[4-chloro-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 93),

N-[1-(3-chloro-4-fluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 95),

N-{1-[4-methyl-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 97),

N-{1-[3-fluoro-5-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 99),

N-{1-[3-chloro-5-(trifluoromethoxy)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 100),

N-[1-(3,5-dichlorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 101), and

N-[1-(3,4-dichlorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 102).

-   [27] The compound according to [1] selected from the following    compounds or a pharmaceutically acceptable salt thereof:

N-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamide(Example 3),

8-fluoro-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 5),

N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Example 6),

N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide(Example 10),

N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide(Example 11),

N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 12), and

N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide(Example 13).

-   [28] A medicament comprising the compound according to any one of    [1] to [27] or a pharmaceutically acceptable salt thereof as an    active ingredient.-   [29] An anti-tumor agent comprising the compound according to any    one of [1] to [27] or a pharmaceutically acceptable salt thereof as    an active ingredient.-   [30] The anti-tumor agent according to [29], wherein the tumor is    acute leukemia, chronic lymphatic leukemia, chronic myelocytic    leukemia, polycythemia vera, malignant lymphoma, myeloma, brain    tumor, head and neck cancer, esophageal cancer, thyroid cancer,    small-cell lung cancer, non-small cell lung cancer, breast cancer,    stomach cancer, gallbladder or bile duct cancer, liver cancer,    pancreatic cancer, colon cancer, rectal cancer, ovarian cancer,    chorioepithelioma, endometrial cancer, cervical cancer, urothelial    cancer, renal cell cancer, prostate cancer, testicular tumor, Wilms'    tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's    sarcoma, or soft tissue sarcoma.-   [31] A medicament comprising the compound according to any one of    [1] to [27] or a pharmaceutically acceptable salt thereof in    combination with another anti-cancer agent selected from the group    consisting of an anticancer alkylating agent, an anticancer    antimetabolite, an anticancer antibiotic, a plant-based anti-cancer    agent, an anticancer platinum coordination compound, an anticancer    camptothecin derivative, an anticancer tyrosine kinase inhibitor, a    serine-threonine kinase, a phospholipid kinase, a monoclonal    antibody, an interferon, a biological response modifier, a hormone    preparation, an immune checkpoint inhibitor, an epigenetics-related    molecule inhibitor, a post-translational protein modification    inhibitor, and an anti-cancer agent other than the foregoings or a    pharmaceutically acceptable salt thereof.-   [32] A method for treating cancer which comprises administering a    therapeutically effective amount of the compound according to any    one of [1] to [27] or a pharmaceutically acceptable salt thereof to    a patient in need thereof.-   [33] Use of the compound according to any one of [1] to [27] or a    pharmaceutically acceptable salt thereof for the manufacture of an    agent for treating cancer.-   [34] A pharmaceutical composition for the treatment of cancer    comprising the compound according to any one of [1] to [27] or a    pharmaceutically acceptable salt thereof.-   [35] The compound according to any one of [1] to [27] or a    pharmaceutically acceptable salt thereof for the use in treating    cancer.

Effects of the Invention

The present compound has a potent inhibitory effect on thesphere-forming ability of cancer cells. In addition, the preferredpresent compound has high biological availability (bioavailability)after oral administration. Thus, the present compound is useful as anorally-available anti-cancer agent.

DESCRIPTION OF EMBODIMENTS

Hereinafter, the present invention is explained in detail. The number ofcarbon atoms in the definition of the “substituent” used herein may beexpressed as, for example, “C₁₋₆”. Specifically, the term “C₁₋₆ alkyl”is used for the same meaning as alkyl group having 1 to 6 carbon atoms.

Specific examples of “halogen atom” used herein include fluorine atom,chlorine atom, bromine atom, and iodine atom.

The term “C₁₋₆ alkyl group” used herein means a straight or branched,saturated hydrocarbon group having 1 to 6 carbon atoms. Preferredexamples thereof include “C₁₋₄ alkyl group”. Specific examples of the“C₁₋₆ alkyl group” include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, and 2-ethylbutyl.

The term “C₁₋₄ alkylene group” used herein means a straight or branched,divalent saturated hydrocarbon group having 1 to 4 carbon atoms, or adivalent saturated hydrocarbon group containing a cyclic structurehaving 3 to 4 carbon atoms.

Specific examples of the straight or branched “C₁₋₄ alkylene group”include methylene, ethylene, trimethylene, tetramethylene,1-methylmethylene, 1-ethylmethylene, 1-propylmethylene,1-methylethylene, 2-methylethylene, and 1-ethylethylene. Preferredexamples thereof include methylene and ethylene.

Specific examples of the “C₁₋₄ alkylene group” containing a cyclicstructure include the following groups:

The “C₁₋₆ alkyl” moiety of the term “C₁₋₆ alkoxy group” used herein isas defined in the above “C₁₋₆ alkyl”. Preferred examples thereof include“C₁₋₄ alkoxy group”. Specific examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, and tert-butoxy.

The term “C₃₋₁₀ cycloalkyl group” used herein means a to 10-memberedmonocyclic or polycyclic, saturated or partially-unsaturated hydrocarbongroup. The group is preferably “C₃₋₇ cycloalkyl group”, and morepreferably cyclohexyl group. Specific examples of the “C₃₋₁₀ cycloalkylgroup” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, cyclohexenyl, decalinyl, adamantyl, andnorbornyl.

The term “C₆₋₁₀ aryl group” used herein means an aromatic hydrocarbongroup having 6 to 10 carbon atoms. The group is preferably “C₆ arylgroup” (phenyl). Specific examples of the “C₆₋₁₀ aryl group” includephenyl, 1-naphthyl, or 2-naphthyl.

Examples of the term “5- to 10-membered heteroaryl group” used hereininclude a 5- to 10-membered mono- or bi-cyclic aromatic group whichcontains the same or different one or more (e.g. 1 to 4) heteroatomsselected from the group consisting of nitrogen atom, sulfur atom, andoxygen atom. The bicyclic heteroaryl group also encompasses a fused ringgroup of a monocyclic heteroaryl group mentioned above with an aromaticgroup (such as benzene and pyridine) or a non-aromatic ring (such ascyclohexyl and piperidine). Specific examples of the “heteroaryl group”include the groups of the following formulae:

The bond across a ring in the above formulae means that a “group” islinked at any replaceable position in the ring. For example, when agroup is the heteroaryl group of the following formula:

the group means 2-pyridyl group, 3-pyridyl group, or 4-pyridyl group.

Furthermore, when a “heteroaryl group” is a bicyclic group, for example,the group of the following formula:

the group may be 1-benzimidazolyl, 2-benzimidazolyl, or 4-, 5-, 6- or7-benzimidazolyl.

In the groups of formulae (11), (12) and (13) defined in the above [1],the two atoms indicated by arrows, which are shared between ring Q² orring Q³ and another ring fused with the ring, are carbon.

The term “aminocarbonyl group” used herein means a formyl group whereinhydrogen atom therein is replaced with amino group.

The “C₁₋₆ alkyl” moiety of the term “C₁₋₆ alkyl-carbonylamino group”used herein is as defined in the above “C₁₋₆ alkyl”. Preferred examplesthereof include “C₁₋₄ alkyl-carbonylamino group”, more preferablymethylcarbonylamino group (acetamido group).

The “C₆₋₁₀ aryl” moiety of the term “C₆₋₁₀ aryloxy group” is as definedin the above “C₆₋₁₀ aryl”. Preferred examples thereof include “C₆aryloxy group” (phenoxy group).

The “C₁₋₆ alkoxy” moiety of the term “C₁₋₆ alkoxy-carbonyl group” usedherein is as defined in the above “C₁₋₆ alkoxy”. Preferred examplesthereof include “C₁₋₄ alkoxy-carbonyl group”. Specific examples of the“C₁₋₆ alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl,and propoxycarbonyl.

The “C₁₋₆ alkyl” moiety of the term “C₁₋₆ alkyl-carbonyl group” usedherein is as defined in the above “C₁₋₆ alkyl”. Preferred examplesthereof include “C₁₋₄ alkyl-carbonyl group”. Specific examples of the“C₁₋₆ alkyl-carbonyl group” include acetyl, ethylcarbonyl, andpropylcarbonyl.

The “C₁₋₆ alkyl” moiety of the term “C₁₋₆ alkylsulfonyl group” usedherein is as defined in the above “C₁₋₆ alkyl”. Preferred examplesthereof include “C₁₋₄ alkylsulfonyl group”. Specific examples of the“C₁₋₆ alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, andpropylsulfonyl.

The “C₁₋₆ alkyl” moiety of the term “C₁₋₆ alkylsulfonylamino group” usedherein is as defined in the above “C₁₋₅ alkyl”. Preferred examplesthereof include “C₁₋₄ alkylsulfonylamino group”. Specific examples ofthe “C₁₋₆ alkylsulfonylamino group” include methylsulfonylamino,ethylsulfonylamino, and propylsulfonylamino.

The “C₁₋₆ alkoxy” moiety of the term “C₁₋₆ alkoxy-carbonylamino group”used herein is as defined in the above “C₁₋₆ alkoxy”. Preferred examplesthereof include “C₁₋₄ alkoxy-carbonylamino group”. Specific examples ofthe “C₁₋₆ alkoxy-carbonylamino group” include methoxycarbonylamino,ethoxycarbonylamino, and propoxycarbonylamino.

The term “C₁₋₆ alkyl-carbonyloxy group” used herein means an oxy groupsubstituted with the above “C₁₋₆ alkyl-carbonyl group”. Preferredexamples thereof include “C₁₋₄ alkyl-carbonyloxy group”. Specificexamples of the “C₁₋₆ alkyl-carbonyloxy group” include acetoxy,propionyloxy, and butyryloxy.

The term “aminosulfonyl group” used herein means a sulfo group whereinhydroxy group therein is substituted with amino group.

Examples of the substituent in the term “optionally-substituted C₁₋₄alkylene group” include hydroxy group, halogen atom, C₃₋₇ cycloalkylgroup, and C₁₋₆ alkoxy group, preferably fluorine atom.

Examples of the substituent in the terms “optionally-substituted C₅₋₁₀aryl group”, “optionally-substituted C₃₋₁₀ cycloalkyl group”,“optionally-substituted 5- to 10-membered heteroaryl group”,“optionally-substituted benzene ring”, “optionally-substituted pyridinering”, “optionally-substituted pyrimidine ring”, “optionally-substitutedpyridazine ring”, “optionally-substituted pyrazine ring”,“optionally-substituted 5-membered heteroaryl ring” include

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same ordifferent 1 to 3 groups selected from the group consisting of halogenatom, hydroxy, and C₁₋₆ alkoxy,

(c) C₁₋₆ alkoxy which may be optionally substituted with the same ordifferent 1 to 3 groups selected from the group consisting of halogenatom, hydroxy, and C₁₋₆ alkoxy,

(d) cyano,

(e) C₆₋₁₀ aryl which may be optionally substituted with the same ordifferent 1 to 4 groups selected from the group consisting of halogenatom, C₁₋₆ alkyl, and C₁₋₆ alkoxy, and

(f) 5- or 6-membered heteroaryl which may be optionally substituted withthe same or different 1 to 4 groups selected from the group consistingof halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(g) C₆₋₁₀ aryloxy which may be optionally substituted with the same ordifferent 1 to 4 groups selected from the group consisting of halogenatom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(h) hydroxy,

(i) amino which may be optionally substituted with the same or different1 to 2 C₁₋₆ alkyl groups,

(j) aminocarbonyl wherein the amino moiety thereof may be optionallysubstituted with the same or different 1 to 2 C₁₋₆ alkyl groups,

(k) C₁₋₆ alkoxy-carbonyl wherein the alkoxy moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(l) C₁₋₆ alkyl-carbonyl wherein the alkyl moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(m) C₁₋₆ alkylsulfonyl wherein the alkyl moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(n) C₁₋₆ alkyl-carbonylamino wherein the alkyl moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(o) C₁₋₆ alkylsulfonylamino wherein the alkyl moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(p) C₁₋₆ alkoxy-carbonylamino wherein the alkoxy moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(q) C₁₋₆ alkyl-carbonyloxy wherein the alkyl moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(r) aminosulfonyl wherein the amino moiety thereof may be optionallysubstituted with the same or different 1 to 2 C₁₋₆ alkyl groups, and

(s) C₃₋₁₀ cycloalkyl which may be optionally substituted with the sameor different 1 to 4 groups selected from the group consisting of halogenatom, hydroxy, and C₁₋₆ alkoxy.

In the present compound of formula (1), W¹, W², R¹, R², R⁴, X, n, m, p,ring Q¹, and Cy¹ are preferably those shown below, but the technicalscope of the present invention should not be limited to the followingcompounds.

W¹ is preferably C₁₋₄ alkylene group which may be optionally substitutedwith the same or different 1 to 4 groups selected from the groupconsisting of halogen atom, hydroxy, and C₁₋₆ alkoxy. W¹ is morepreferably methylene group which may be optionally substituted with thesame or different 1 to 2 halogen atoms or ethylene group which may beoptionally substituted with the same or different 1 to 4 halogen atoms,furthermore preferably methylene group.

W²-Cy¹ preferably includes —NR^(3a)C(O)-Cy¹ or C(O)NR^(3a)-Cy¹ whereinR^(3a) is hydrogen atom or C₁₋₆ alkyl group. W²-Cy¹ is more preferably—NHC(O)—Cy¹ or —C(O)NH-Cy¹, furthermore preferably —NHC(O)-Cy¹.

Preferably, R¹ and R² independently includes hydrogen atom, halogenatom, C₁₋₄ alkyl group which may be optionally substituted with the sameor different 1 to 3 halogen atoms. R¹ and R² are more preferablyhydrogen atom, chlorine atom, or methyl group, furthermore preferablyhydrogen atom.

Ring Q¹ preferably includes

-   (1) C₆₋₁₀ aryl group which may be optionally substituted with the    same or different 1 to 4 groups selected from the group consisting    of:

(a) halogen atom,

(b) C₁₋₅ alkyl which may be optionally substituted with the same ordifferent 1 to 3 groups selected from the group consisting of halogenatom, hydroxy, and C₁₋₆ alkoxy,

(c) C₁₋₆ alkoxy which may be optionally substituted with the same ordifferent 1 to 3 groups selected from the group consisting of halogenatom, hydroxy, and C₁₋₆ alkoxy,

(d) cyano,

(e) phenyl which may be optionally substituted with the same ordifferent 1 to 4 groups selected from the group consisting of halogenatom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(f) 5- or 6-membered heteroaryl which may be optionally substituted withthe same or different 1 to 4 groups selected from the group consistingof halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(g) phenoxy which may be optionally substituted with the same ordifferent 1 to 4 groups selected from the group consisting of halogenatom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(h) hydroxy,

(i) amino which may be optionally substituted with the same or different1 to 2 alkyl groups, and

(j) aminocarbonyl wherein the amino moiety thereof may be optionallysubstituted with the same or different 1 to 2 C₁₋₆ alkyl groups,

-   (2) C₃₋₁₀ cycloalkyl group which may be optionally substituted with    the same or different 1 to 5 groups selected from the group    consisting of (a) to (j) defined in the above (1), or-   (3) 5- to 10-membered heteroaryl group which may be optionally    substituted with the same or different 1 to 5 groups selected from    the group consisting of (a) to (j) defined in the above (1).

Ring Q¹ preferably includes

-   (1) phenyl group which may be optionally substituted with the same    or different 1 to 5 groups selected from the group consisting of:

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same ordifferent 1 to 3 groups selected from the group consisting of halogenatom, hydroxy, and C₁₋₆ alkoxy,

(c) C₁₋₆ alkoxy which may be optionally substituted with the same ordifferent 1 to 3 groups selected from the group consisting of halogenatom, hydroxy, and C₁₋₆ alkoxy,

(d) cyano,

(e) phenyl which may be optionally substituted with the same ordifferent 1 to 4 groups selected from the group consisting of halogenatom, C₁₋₆ alkyl, and C₁₋₆ alkoxy, and

(f) 5- or 6-membered heteroaryl which may be optionally substituted withthe same or different 1 to 4 groups selected from the group consistingof halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy, or

-   (2) pyridyl group which may be optionally substituted with the same    or different 1 to 4 groups selected from the group consisting of (a)    to (f) defined in the above (1).

Ring Q¹ furthermore preferably includes phenyl group which may beoptionally substituted with the same or different 1 to 5 groups selectedfrom the group consisting of:

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same ordifferent 1 to 3 halogen atoms, and

(c) C₁₋₆ alkoxy which may be optionally substituted with the same ordifferent 1 to 3 halogen atoms.

Cy¹ preferably includes the group of formula (11) in the above [1].

Preferred aspects of the group of formula (11) in the above [1] includethe group of formula (21) in the above [9].

More preferably, it includes the following groups:

wherein R⁴, n, m, and p are as defined in the above [1]; and R, R¹³ andR¹⁴ are as defined in the above [9].

Furthermore preferably, it includes the above groups of formulae (21a),(21b), (21c) and (21d).

Preferred aspects of the group of formula (12) in the above [1] includethe group of formula (22) in the above [9].

More preferably, it includes the following groups:

wherein R⁴, n, m, and p are as defined in the above [1]; and R¹⁵ is asdefined in the above [9].

It furthermore preferably includes the above groups of formulae (22a)and (22b), most preferably the above group of formula (22a).

Preferred aspects of the group of formula (13) in the above [1] includethe group of formula (23) in the above [9].

More preferably, it includes the following groups:

wherein R⁴, n, and p are as defined in the above [1]; and R12, R¹³, andR¹⁴ are as defined in the above [9].

Furthermore preferably, it includes the above group of formula (23a).

R⁴ preferably includes hydrogen atom, fluorine atom, or C₁₋₄ alkyl. R⁴is more preferably hydrogen atom.

p in the above [1] and q in the above [9] are independently selectedfrom 1, 2, 3, 4, or 5. Preferably, p and q are independently 1, 2, or 3.When the number of the replaceable positions on the ring having thesubstituent R⁴ or R¹¹ is less than 5, p and q are independently selectedfrom the maximum replaceable number of R⁴ or R¹¹. For example, when ringQ¹ is pyridyl group, q is selected from 1, 2, 3, or 4.

X preferably includes NR⁵ wherein R⁵ is hydrogen atom or C₁₋₆ alkylgroup which may be optionally substituted with the same or different 1to 3 halogen atoms, and more preferably it is NH.

With regard to n and m, preferably n is 1 and m is 1; or n is 2 and m is0. More preferably, n is 1 and m is 1.

The present compound may be in the forms of a hydrate and/or a solvate.Thus, the present compound also encompasses hydrate and/or solvate suchas ethanol solvate. Furthermore, the present compound encompasses alltypes of crystal forms of the present compound.

Specific examples of the pharmaceutically acceptable salt of thecompound of formula (1) include an inorganic acid salt such ashydrochloride, hydrobromide, sulfate, phosphate, and nitrate; and anorganic acid salt such as acetate, propionate, oxalate, succinate,lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate,p-toluenesulfonate, benzenesulfonate, and ascorbate.

The compound of formula (1) may be in the form of a tautomer. Thus, thepresent compound also encompasses the tautomer of the compound offormula (1).

The compound of formula (1) may contain one or more asymmetric carbonatoms. Thus, the present compound encompasses not only racemic forms ofthe compound of formula (1) but also optically-active forms thereof.When the compound of formula (1) contains two or more asymmetric carbonatoms, the compound can result in various stereoisomerisms. Thus, thepresent compound also encompasses the stereoisomer of the compound and amixture or isolate thereof.

Also, the compound of formula (1) encompasses the compound wherein oneor more of ¹H are replaced with ²H(D) (i.e. deuterated form).

Preparations

The present compounds can be prepared according to processes shown belowand according to the processes in combination with known compounds andknown synthesis processes.

As appropriate, each compound used as a starting compound may be used inthe salt form. The shown processes are just examples to prepare thecompounds, and may be optionally modified by those skilled in theorganic synthesis field.

In each process shown below, any functional groups which need to beprotected may be optionally protected and then deprotected after thereaction or reactions are completed to give the desired compound eventhough the use of protective groups is not specifically described.

The protective group used herein includes any conventional groupsdescribed in various literatures, for example, T. W. Greene and P. G. M.Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley andSons, inc., New York (1999). In more detail, specific examples of theprotective groups for amino group include benzyloxycarbonyl,tert-butoxycarbonyl, acetyl, and benzyl, and specific examples of theprotective groups for hydroxy group include trialkylsilyl, acetyl, andbenzyl.

The protective groups can be introduced and cleaved according tocommonly-used methods in synthetic organic chemistry (e.g. the methoddescribed in T. W. Greene and P. G. M. Nuts, “Protective Groups inOrganic Synthesis”, 3rd Ed., John Wiley and Sons, inc., New York (1999))and similar methods thereto.

Preparation 1

One of the compounds of formula (1), the compound of formula (1-8) isprepared by linking each fragment in positions a, b and c, respectively:

wherein W¹, R¹, R², R⁴, R⁵, n, m, p, ring Q¹, and ring Q² are as definedin the above [1].

The processes for forming each bond in positions a, b and c can beillustrated as follows, but the order of procedure for forming each bondmay be optionally changed:

wherein W¹, R¹, R², R⁴, R⁵, n, m, p, ring Q¹, and ring Q² are as definedin the above [1]; L is a leaving group (such as iodine atom, bromineatom, chlorine atom and substituted sulfonyl group (e.g. methanesulfonylgroup and p-toluenesulfonyl group)); and R¹⁰¹ is benzyloxycarbonyl (Cbz)group, Boc group, benzyl group, 4-methoxybenzyl group, or9-fluorenylmethyloxycarbonyl (Fmoc) group.

Compound (1-1) may be a commercially available product or be preparedaccording to known synthesis processes (e.g. New Version of HeterocyclicCompound (advanced level) edited by Kodansha Scientific Ltd.).

Step 1-1: Preparation Process of Compound (1-3)

Compound (1-3) is prepared by the alkylation reaction of compound (1-1)with compound (1-2) in an inert solvent in the presence of a base.

Specific examples of the base include an organic base such astriethylamine, diisopropylethylamine, and pyridine; an inorganic basesuch as potassium carbonate, sodium carbonate, cesium carbonate,potassium hydrogen carbonate, sodium hydrogen carbonate, potassiumdihydrogen phosphate, dipotassium hydrogen phosphate, potassiumphosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate,sodium phosphate, potassium hydroxide, sodium hydroxide, and sodiumhydride; and a metal alkoxide such as sodium methoxide and potassiumtert-butoxide.

Specific examples of the inert solvent include a halogenated hydrocarbonsuch as chloroform and dichloromethane; an aromatic hydrocarbon such astoluene; an ether-type solvent such as diethyl ether, tetrahydrofuran(THF), and 1,4-dioxane; an aprotic polar solvent such as acetonitrile,acetone, methyl ethyl ketone, N,N-dimethylformamide,N-methyl-2-pyrrolidinone, and dimethylsulfoxide; a basic solvent such aspyridine; and a mixture thereof.

The reaction temperature is typically 0° C. to 150° C., preferably 20°C. to 100° C., but is not limited thereto. The reaction time istypically 30 minutes to 48 hours, preferably 30 minutes to 10 hours.

Step 1-2: Preparation Process of Compound (1-4)

Compound (1-4) is prepared by reducing the nitro group in compound(1-3). For example, reactions such as reduction under an acidiccondition with a metal such as zinc, iron and tin or a metal salt suchas tin (II) chloride; reduction with a sulfide such as sodium dithionite(Na₂S₂O₄); or catalytic hydrogenation with a metal catalyst such aspalladium/carbon, Raney nickel, platinum oxide/carbon, andrhodium/carbon under hydrogen atmosphere are used.

In the reduction reaction with a metal or a metal salt, the amount ofthe metal or the metal salt to be used is typically about 1 mole to 100moles, preferably about 10 moles to 30 moles per mole of compound (1-3).Also, the amount of the acid to be used is typically about 1 mole to 100moles, preferably about 10 moles to 30 moles per mole of compound (1-3).The reduction reaction is typically carried out in a solvent which hasno negative effect on the reaction (e.g. ethanol). The reactiontemperature is typically 0° C. to 100° C., but is not limited thereto.The reaction time is typically 30 minutes to 8 hours.

In the catalytic hydrogenation reaction, the amount of the metalcatalyst to be used for compound (1-3) is typically 0.1% by weight to1000% by weight, preferably 1% by weight to 100% by weight. The reactionmay be carried out in a solvent such as an alcohol such as methanol; anether such as tetrahydrofuran; and an ester such as ethyl acetate. Thehydrogen pressure is typically 1 atm to 100 atms, preferably 1 atm to 5atms. The reaction temperature is typically 0° C. to 120° C., preferably20° C. to 80° C., but is not limited thereto. The reaction time istypically 30 minutes to 72 hours, preferably 1 hour to 48 hours.

Also, the reaction may be carried out in the presence of an acidcatalyst, as appropriate. For example, an organic acid such as formicacid, acetic acid and trifluoroacetic acid, and an inorganic acid suchas sulfuric acid, hydrochloric acid and hydrobromic acid are used as theacid catalyst. The amount of the acid to be used is 0.1 mole or more permole of compound (1-3).

Step 1-3: Preparation Process of Compound (1-6)

Compound (1-6) is prepared by reacting compound (1-4) with compound(1-5) in an inert solvent in the presence of a condensation agent.

The reaction may be carried out in the presence of a base, asappropriate. The reaction temperature is typically about −20° C. to theboiling point of the used solvent, but is not limited thereto. Thereaction time is typically 10 minutes to 48 hours, which may varyaccording to various conditions such as a reaction temperature, acondensation agent, a starting material, and a solvent to be used.

Specific examples of the condensation agent includedicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC),benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate(BOP), diphenylphosphonyl diamide (DPPA), N,N-carbonyldiimidazole (CDI),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU). As appropriate, the reaction may be carriedout with the addition of an additive such as N-hydroxysuccinimide(HOSu), 1-hydroxybenzotriazole (HOBt), and3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt).

Specific examples of the base include an organic base such astriethylamine, diisopropylethylamine and pyridine; an inorganic basesuch as potassium carbonate, sodium carbonate, cesium carbonate,potassium hydrogen carbonate, sodium hydrogen carbonate, potassiumdihydrogen phosphate, dipotassium hydrogen phosphate, potassiumphosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate,sodium phosphate, potassium hydroxide, sodium hydroxide and sodiumhydride; and a metal alkoxide such as sodium methoxide and potassiumtert-butoxide.

Specific example of the inert solvent include a halogenated hydrocarbonsuch as chloroform and dichloromethane; an aromatic hydrocarbon such astoluene; an ether-type solvent such as diethyl ether, tetrahydrofuran(THF) and 1,4-dioxane; an aprotic polar solvent such as acetonitrile,acetone, methyl ethyl ketone, dimethylformamide,N-methyl-2-pyrrolidinone and dimethylsulfoxide; a basic solvent such aspyridine; and a mixture thereof.

Compound (1-6) is also prepared by reacting compound (1-4) with an acidhalide or an acid anhydride derived from compound (1-5) in an inertsolvent in the presence of a base.

Step 1-4: Preparation Process of Compound (1-7)

Compound (1-7) is prepared using compound (1-6) as the starting materialaccording to a similar process to the process described in literatures(such as Protective Groups in Organic Synthesis 3^(rd) Edition (JohnWiley & Sons, Inc.)).

Step 1-5: Preparation Process of Compound (1-8)

Compound (1-8) is prepared by the reductive amination of compound (1-7)with an alkylketone or an alkylaldehyde in an appropriate inert solventin the presence of a reducing agent.

The reaction may be carried out in the presence of a base, an acid orother additives, as appropriate. The reaction temperature is typicallyabout −20° C. to the boiling point of the used solvent. The reactiontime is typically 10 minutes to 48 hours, which may vary according tovarious conditions such as a reaction temperature, a reducing agent, astarting material, and a solvent to be used.

Specific examples of the reducing agent include sodium cyanoborohydride,sodium triacetoxyborohydride, and sodium borohydride.

Specific examples of the base include an organic base such astriethylamine, diisopropylethylamine and pyridine; and an inorganic basesuch as potassium carbonate, sodium carbonate, cesium carbonate,potassium hydrogen carbonate, sodium hydrogen carbonate, potassiumdihydrogen phosphate, dipotassium hydrogen phosphate, potassiumphosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate,sodium phosphate, potassium hydroxide, sodium hydroxide and sodiumhydride.

Specific examples of the acid include an organic acid such as aceticacid, trifluoroacetic acid and methanesulfonic acid; and an inorganicacid such as hydrochloric acid and sulfuric acid.

Specific examples of the solvent include water; acetonitrile; ahalogenated hydrocarbon such as chloroform and dichloromethane; anaromatic hydrocarbon such as benzene and toluene; an ether-type solventsuch as 1,2-dimethoxyethane, tetrahydrofuran and 1,4-dioxane; analcohol-type solvent such as methanol, ethanol and 2-propanol; anaprotic polar solvent such as dimethylformamide andN-methyl-2-pyrrolidinone; and a mixture thereof.

Preparation 2

The compound of formula (2-5) is prepared according to, for example, thefollowing process.

wherein R⁴, n, m, p, and ring Q² are as defined in the above [1]; X^(a)is O or NR¹⁰¹; R¹⁰¹ is Cbz group, Boc group, benzyl group,4-methoxybenzyl group or Fmoc group; R¹⁰² is C₁₋₆ alkyl group; and L isa leaving group (such as iodine atom, bromine atom, chlorine atom andsubstituted sulfonyl group (e.g. methanesulfonyl group andp-toluenesulfonyl group)).

Compound (2-1) may be a commercially available product or be preparedaccording to known synthesis processes (e.g. WO 2009/056556, WO2006/065215).

Step 2-1: Preparation Process of Compound (2-3)

Compound (2-3) is prepared by introducing ester group to compound (2-1)under carbon monoxide atmosphere in the presence of palladium catalyst,phosphorus ligand, an alcohol of formula (2-2) in an inert solvent.

The pressure of carbon monoxide is selected according to variousconditions such as a reaction temperature, a starting material, and asolvent to be used, as appropriate, and is typically 1 atm to 100 atms,preferably 1 atm to 5 atms. The reaction temperature is typically about−20° C. to the boiling point of the used solvent, preferably roomtemperature to the boiling point of the used solvent. The reaction maybe carried out using a microwave reaction device. The reaction time istypically 10 minutes to 48 hours, which may vary according to variousconditions such as a reagent, a reaction temperature, a startingmaterial, and a solvent to be used.

Examples of the palladium catalyst includetetrakis(triphenylphosphine)palladium anddi-tert-butylphosphinepalladium.

Examples of the inert solvent include N,N-dimethylformamide,N-methyl-2-pyrrolidinone, 1,4-dioxane and a mixture thereof.

In addition, an organic base such as N,N-diisopropylethylamine andtriethylamine may be added thereto, as appropriate.

Step 2-2: Preparation Process of Compound (2-5)

Compound (2-5) is prepared by hydrolyzing compound (2-3) according to asimilar process to a known process (e.g. Protective Groups in OrganicSynthesis 3^(rd) Edition (John Wiley & Sons, Inc.), ComprehensiveOrganic Transformation, by R. C. Larock et al., VCH publisher Inc.,1989).

Step 2-3: Preparation Process of Compound (2-4)

Compound (2-4) is prepared by the cyanation of compound (2-1) in aninert solvent in the presence of palladium catalyst, phosphorus ligandand a cyanating agent.

The reaction temperature is typically about −20° C. to the boiling pointof the used solvent, preferably room temperature to the boiling point ofthe used solvent. The reaction may be carried out using a microwavereaction device. The reaction time is typically 10 minutes to 48 hours,which may vary according to various conditions such as a reactiontemperature, a reagent, a starting material, and a solvent to be used.

Examples of the cyanating agent include sodium cyanide, potassiumcyanide and zinc cyanide, preferably zinc cyanide.

Examples of the palladium catalyst includetetrakis(triphenylphosphine)palladium anddi-tert-butylphosphinepalladium.

Examples of the inert solvent include N,N-dimethylformamide,N-methyl-2-pyrrolidinone, 1,4-dioxane and a mixture thereof.

Step 2-4: Preparation Process of Compound (2-5)

Compound (2-5) is prepared by hydrolyzing the cyano group in compound(2-4) in an appropriate solvent in the presence of a base.

The reaction temperature is typically about −20° C. to the boiling pointof the used solvent, preferably room temperature to the boiling point ofthe used solvent. The reaction time is typically 10 minutes to 48 hours,which may vary according to various conditions such as a reactiontemperature, a starting material, and a solvent to be used.

Examples of the base include sodium hydroxide and potassium hydroxide.

Examples of the solvent to be used include methanol, ethanol,2-propanol, acetone, tetrahydrofuran, 1,4-dioxane, water and a mixturethereof.

Preparation 3

The compound of formula (3-6) is prepared by, for example, the followingprocess.

wherein ring Q² is as defined in the above [1]; A is boronic acid orboronate; R¹⁰² is C₁₋₆ alkyl group, R¹⁰³ is C₁₋₆ alkyl group, benzylgroup, allyl group, etc.; R^(a) and R^(b) are the same or differenthydrogen atom or methyl group; and X is halogen atom.

Step 3-1: Preparation Process of Compound (3-3)

Compound (3-3) is prepared by reacting compound (3-1) with compound(3-2) in an inert solvent in the presence of palladium catalyst and abase.

Specific examples of the palladium catalyst includetetrakis(triphenylphosphine)palladium (0),bis(dibenzylideneacetone)palladium (0),tris(dibenzylideneacetone)dipalladium (0),bis(tri-tert-butylphosphine)palladium (0),[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride.

Examples of the base include an inorganic base such as potassiumcarbonate, sodium carbonate, cesium carbonate, potassium phosphate,potassium hydroxide and sodium hydroxide.

Examples of the inert solvent include toluene, 1,2-dimethoxyethane,1,4-dioxane, DMF and a mixture thereof.

The reaction temperature is typically about 50° C. to 150° C.,preferably 80° C. to 120° C., but is not limited thereto.

Also, the reaction may be carried out under microwave irradiation. Thereaction time is typically 1 hour to 24 hours, preferably 2 hours to 12hours.

Step 3-2: Preparation Process of Compound (3-4)

Compound (3-4) is prepared by reacting compound (3-3) with osmiumtetroxide or potassium osmate (IV) dihydrate in the presence of sodiumperiodate.

Examples of the solvent to be used include acetone, 1,4-dioxane, THF,tert-butanol, water and a mixture thereof.

The reaction temperature is typically about 0° C. to 100° C., preferably25° C. to 50° C., but is not limited thereto. The reaction time istypically 1 hour to 72 hours, preferably 6 hours to 24 hours.

Also, compound (3-4) is prepared by treating compound (3-3) with oxygencurrents including ozone and then reacting the treated compound with areducing agent such as dimethyl sulfide at room temperature or −78° C.in a solvent such as dichloromethane, ethyl acetate and methanol. Thereaction temperature is typically −78° C. to room temperature, but isnot limited thereto. The reaction time is typically 1 hour to 72 hours,preferably 6 hours to 24 hours.

Step 3-3: Preparation Process of Compound (3-5)

Compound (3-5) is prepared by reacting compound (3-4) with anorganometallic reagent or a hydride reducing agent.

Specific examples of the organometallic reagent include methyllithiumreagent and methyl Grignard reagent.

Specific examples of the hydride reducing agent include sodiumborohydride and sodium cyanoborohydride.

The solvent used in the reaction with the organometallic reagentincludes THF, diethyl ether and a mixture thereof, and the solvent usedin the reaction with the hydride reducing agent includes methanol,ethanol, dichloromethane, toluene and a mixture thereof.

The reaction temperature is typically −78° C. to 50° C., preferably 0°C. to 25° C., but is not limited thereto. The reaction time is typically5 minutes to 12 hours, preferably 30 minutes to 6 hours.

Step 3-4: Preparation Process of Compound (3-6)

Compound (3-6) is prepared by reacting compound (3-5) with aqueousalkali solution.

Examples of the aqueous alkali solution include ageous sodium hydroxidesolution, aqueous potassium hydroxide solution and aqueous lithiumhydroxide solution, and the concentraton thereof is typically 1 to 10mol/L, preferably 1 to 5 mol/L.

Examples of the solvent to be used include methanol, ethanol,2-propanol, THF, 1,4-dioxane and a mixture threof.

The reaction temperature is typically 0° C. to 100° C., preferably 0° C.to 50° C., but is not limited thereto. The reaction time is typically 10minutes to 24 hours, preferably 30 minutes to 12 hours.

Preparation 4

The compound of formula (4-1) may be a commercially available product orbe prepared according to known synthesis processes (e.g. J. Med. Chem.,2004, 5167-5182, Bioorg. Med. Chem., 2006, 1309-1330.).

Preparation 5

One of the compounds of formula (1), the compound of formula (5-5) isprepared according to, for example, the following process.

wherein W^(1I), R¹, R², R⁴, n, m, p, ring Q², and ring Q² are as definedin the above [1]; R¹⁰¹ is Cbz group, Boc group, benzyl group,4-methoxybenzyl group or Fmoc group; and R¹⁰² is C₁₋₆ alkyl group.

The compound of formula (5-1) may be a commercially available product orbe prepared according to known synthesis processes (e.g. WO2014/125444).

Step 5-1: Preparation Process of Compound (5-2)

Compound (5-2) is prepared by hydrolyzing compound (5-1) according to asimilar process to a known process (e.g. Protective Groups in OrganicSynthesis 3^(rd) Edition (John Wiley & Sons, Inc.), ComprehensiveOrganic Transformation, by R. C. Larock et al., VCH publisher Inc.,1989).

Step 5-2: Preparation Process of Compound (5-4)

Compound (5-4) is prepared from compounds (5-2) and (5-3) according tothe process of Step 1-3.

Step 5-3: Preparation Process of Compound (5-5)

Compound (5-5) is prepared using compound (5-4) as a starting materialaccording to a simialr process to the process described in literatures(such as Protective Groups in Organic Synthesis 3^(rd) Edition (JohnWiley & Sons, Inc.)).

Preparation 6

The compound of formula (1-6) is prpared by, for example, the followingprocess.

wherein W¹, R¹, R², R⁴, n, m, p, ring Q¹, and ring Q² are as defined inthe above [1]; L is a leaving group (such as iodine atom, bromine atom,chlorine atom and substituted sulfonyloxy group (e.g. methanesulfonyloxygroup and p-toluenesulfonyloxy group)); and R¹⁰¹ and R¹⁰⁴ arebenzyloxycarbonyl (Cbz) group, Boc group, benzyl group, 4-methoxybenzylgroup, 2-(trimethylsilyl)ethoxymethyl group or9-fluorenylmethyloxycarbonyl (Fmoc) group.

Step 6-1: Preparation Process of Compound (6-1)

Compound (6-1) is prepared by introducing a protective group to N atomof the imidazole group in compound (1-1) in an inert solvent. Examplesof the protective group include 2-(trimethylsilyl)ethoxymethyl,benzyloxycarbonyl, tert-butoxycarbonyl, acetyl and benzyl.

For example, when 2-(trimethylsilyl)ethoxymethyl group is introduced,compound (6-1) is prepared by reacting compound (1-1) with2-(trimethylsilyl)ethoxymethyl chloride in an inert solvent in thepresence of a base.

Examples of the base include potassium carbonate, sodium carbonate,cesium carbonate, potassium-tert-butoxide, sodium hydroxide, sodiumbis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide and lithium diisopropylamide. Examples of theinert solvent include DMF, THF, acetonitrile and a mixture thereof.

The reaction temperature is typically 0° C. to 150° C., preferably 0° C.to 100° C., but is not limited thereto. The reaction time is typically10 minutes to 24 hours, preferably 20 minutes to 6 hours.

Step 6-2: Preparation Process of Compound (6-2)

Compound (6-2) is prepared from compound (6-1) according to the processof Step 1-2.

Step 6-3: Preparation Process of Compound (6-3)

Compound (6-3) is prepared from compounds (6-2) and (1-5) according tothe process of Step 1-3.

Step 6-4: Preparation Process of Compound (6-4)

Compound (6-4) is prepared by cleaving the protective group for nitrogenatom of the imidazole group in compound (6-3) in an inert solvent.

For example, when 2-(trimethylsilyl)ethoxymethyl group is cleaved,compound (6-4) is prepared by reacting compound (6-3) with an acid or afluorinating reagent in an inert solvent.

Examples of the acid include TFA, formic acid, hydrochloric acid,sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and (±)10-camphorsulfonic acid.

Examples of the fluorinating reagent include tetrabutylammoniumfluoride.

Examples of the solvent to be used include dichloromethane,1,2-dichloroethane, 1,4-dioxane, THF, toluene, ethyl acetate, methanol,ethanol, 2-propanol and a mixture thereof.

The reaction temperature is typically 0° C. to 150° C., preferably 0° C.to 50° C., but is not limited thereto. The reaction time is typically 5minutes to 24 hours, preferably 1 hour to 9 hours.

In Step 6-4, when R¹⁰¹ is cleaved simultaneously with cleaving theprotective group for nitrogen atom of the imidazole group, compound(6-4) is prepared by reintroducing a protecting group to R¹⁰¹.

Step 6-5: Preparation Process of Compound (1-6)

Compound (1-6) is prepared from compounds (6-4) and (1-2) according tothe process of Step 1-1.

Preparation 7

One of the compounds of formula (1-5), the compound of formula (7-4) isprepared according to, for example, the following process:

wherein R⁴, p, and ring Q² are as defined in the above [1]; R¹⁰¹ is Cbzgroup, Boc group, benzyl group, 4-methoxybenzyl group, or Fmoc group;and R¹⁰² is C₁₋₆ alkyl group.

Compound (7-1) may be a commercially available product or be preparedaccording to Preparation 8.

Step 7-1: Preparation Process of Compound (7-2)

Compound (7-2) is prepared by reacting compound (7-1) with a hydridereducing agent in an inert solvent.

Specific examples of the hydride reducing agent include sodiumborohydride, sodium cyanoborohydride, borane and hydride aluminiumhydride.

Examples of the solvent to be used in the reaction with the hydridereducing agent include methanol, ethanol, dichloromehane, toluene,tetrahydrofuran and a mixture thereof.

The reaction temperature is typically −78° C. to 100° C., preferably 0°C. to 50° C., but is not limited thereto. The reaction time is typically5 minutes to 12 hours, preferably 30 minutes to 6 hours.

Step 7-2: Preparation Process of Compound (7-3)

Compound (7-3) is prepared by reducing olefin in compound (7-2) with areagent for introducing a protective group. For example, reactions suchas catalytic hydrogenation reaction with a metal catalyst such aspalladium/carbon, Raney nickel, platinum oxide/carbon and rhodium/carbonunder hydrogen atmosphere in the presence of Boc₂O are used.

In the catalytic hydrogenation reaction, the amount of the metalcatalyst to be used for compound (7-2) is typically 0.1% by weight to1000% by weight, preferably 1% by weight to 100% by weight. The reactionmay be carried out in a solvent such as an alcohol such as methanol; anether such as tetrahydrofuran; and an ester such as ethyl acetate. Thehydrogen pressure is typically atm to 100 atms, preferably 1 atm to 5atms. The reaction temperature is typically 0° C. to 120° C., preferably20° C. to 80° C., but is not limited thereto. The reaction time istypically 30 minutes to 72 hours, preferably 1 hour to 48 hours.

When R¹⁰¹ is benzyl group, 4-methoxybenzyl group, etc., compound (7-3)can be directly prepared through a pyridinium salt intermediate ofcompound (7-1). For example, compound (7-3) is prepared by reducing thepyridinium salt of compound (7-1) synthesized by reacting compound (7-1)with a reagent such as benzyl bromide. Reduction reactions such asreduction with a hydride reducing agent and catalytic hydrogenation witha metal catalyst such as palladium/carbon, Raney nickel, platinumoxide/carbon, and rhodium/carbon under hydrogen atmosphere are used.

Step 7-3: Preparation Process of Compound (7-4)

Compound (7-4) is prepared by hydrolyzing compound (7-3) according to asimilar process to a known process (e.g. Protective Groups in OrganicSynthesis 3^(rd) Edition (John Wiley & Sons, Inc.), ComprehensiveOrganic Transformation, by R. C. Larock et al., VCH publisher Inc.,1989).

Preparation 8

One of the compounds of formula (7-1), the compound of formula (8-3) isprepared according to, for example, the following process:

wherein R⁴ and p are as defined in the above [1]; and R¹⁰² and R¹⁰³ areC₁₋₆ alkyl group.

Step 8-1: Preparation Process of Compound (8-3)

Compound (8-3) is prepared by reacting compound (8-1) with compound(8-2) under an acidic condition in an inert solvent.

Examples of the acid used include trifluoroacetic acid, hydrochloricacid and sulfuric acid.

The reaction temperature is typically 0° C. to 150° C., preferably 0° C.to 100° C., but is not limited thereto. The reaction time is typically 5minutes to 72 hours, preferably 30 minutes to 12 hours.

Examples of the inert solvent include dichloromethan,1,2-dichloroethane, chloroform, THF, toluene, ethyl acetate and amixture thereof.

The intermediates and desired compounds in the above preparations may beisolated and purified by a conventional purification method in organicsynthetic chemistry such as neutralization, filtration, extraction,washing, drying, concentration, recrystallization, and each type ofchromatography. The intermediates may be also used in the next reactionwithout any specific purification.

An optically-active product of the present compound can be prepared froman optically-active starting material or intermediate, or by the opticalresolution of the racemate of a final product. The optical resolutionmethod includes a physical separation method with optically-activecolumn, and a chemical separation method such as a fractionalcrystallization method. A diastereomer of the present compound can beprepared by, for example, a fractional crystallization method.

The pharmaceutically acceptable salt of the compound of formula (1) canbe prepared by, for example, mixing the compound of formula (1) with apharmaceutically acceptable acid in a solvent such as water, methanol,ethanol, and acetone.

The present compound is used as, for example, an anti-tumor agent(anti-cancer agent). The applicable cancer type includes hematopoietictumor and solid cancer, but is not limited thereto. Specific examples ofthe hematopoietic tumor include acute leukemia, chronic lymphaticleukemia, chronic myelocytic leukemia, polycythemia vera, malignantlymphoma, and myeloma, and specific examples of the solid cancer includebrain tumor, head and neck cancer, esophageal cancer, thyroid cancer,small-cell lung cancer, non-small cell lung cancer, breast cancer,stomach cancer, gallbladder or bile duct cancer, liver cancer,pancreatic cancer, colon cancer, rectal cancer, ovarian cancer,chorioepithelioma, endometrial cancer, cervical cancer, urothelialcancer, renal cell cancer, prostate cancer, testicular tumor, Wilms'tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma,and soft tissue sarcoma.

The anti-tumor agent is used for the prophylaxis and/or treatment of acancer, and is expected to produce the reduction or disappearance ofcarcinoma or inhibit the growth of carcinoma down to a certain level.The “prophylaxis” used herein means the administration of the activeingredient of the present invention to a healthy subject who does notdevelop a disease. For example, the prophylaxis is intended to preventthe development of a disease. The “treatment” used herein means theadministration of the active ingredient of the present invention to aperson diagnosed with the development of a disease by a doctor (i.e. apatient). For example, the treatment is intended to alleviate a diseaseor symptom thereof, inhibit the growth of carcinoma, or improve thecondition of a patient to the previous condition before a disease isdeveloped. Also, even if an anti-tumor agent is administered for thepurpose of preventing the worsening of a disease or symptom thereof orthe growth of carcinoma, the administration is referred to as“treatment” when the subject to be administered is a patient.

The present compound has any remarkable effects for inhibitingself-renewal ability of CSCs, and thus is expected to be useful as anovel anti-tumor agent for inhibiting the persistent proliferation,metastasis, and recurrence of malignant tumors derived from CSCs.

The present compound may be formulated into a suitable dosage form andadministered orally or parenterally. Examples of the dosage form includea tablet, a capsule, a powder, a granule, a solution, a suspension, aninjection, a patch, and a poultice, but are not limited thereto. Thepreparation is formulated using pharmaceutically acceptable additive(s)according to a known method.

As appropriate, an additive such as an excipient, a disintegrant, abinder, a fluidizer, a lubricant, a coating agent, a solubilizer, asolubilizing agent, a thickening agent, a dispersant, a stabilizingagent, a sweetening agent, and a flavor may be used. Specific examplesthereof include lactose, mannitol, crystalline cellulose, lowsubstituted hydroxypropylcellulose, corn starch, partly pregelatinizedstarch, carmellose calcium, croscarmellose sodium,hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylalcohol,magnesium stearate, sodium stearyl fumarate, polyethylene glycol,propylene glycol, titanium oxide, and talc.

The present compound may be used in combination with another drug(s) toenhance the therapeutic effect thereof and/or reduce side effectsthereof. Specifically, the present compound can be used in combinationwith a drug such as a hormone therapeutic drug, a chemotherapeutic drug,an immunotherapeutic drug or a cell growth factor and a drug forinhibiting a receptor effect thereof. Hereinafter, a drug which can beused in combination with the present compound is referred to as“combined medicine”.

Examples of the combined medicine include an anticancer alkylatingagent, an anticancer antimetabolite, an anticancer antibiotic, aplant-based anti-cancer agent, an anticancer platinum coordinationcompound, an anticancer camptothecin derivative, an anticancer tyrosinekinase inhibitor, a serine-threonine kinase, a phospholipid kinase, amonoclonal antibody, an interferon, a biological response modifier, ahormone preparation, an immune checkpoint inhibitor, anepigenetics-related molecule inhibitor, a post-translational proteinmodification inhibitor, and an anti-cancer agent other than theforegoings.

The administration timing of the present compound and a combinedmedicine is not necessarily limited, and they may be administeredsimultaneously or administered with time-interval to a subject. Inaddition, the present compound and a combined medicine may be used inthe form of a combination drug. The dosage of the combined medicine maybe optionally determined based on the dosage in the clinical use. Also,the mixing ratio of the present compound and a combined medicine may beoptionally determined depending on the subject to be administered, theadministration route, the disease to be treated, the symptom, and acombination thereof. For example, when the subject is human, thecombined medicine may be used in an amount of 0.01 to 100 parts byweight relative to 1 part by weight of the present compound. Inaddition, a drug (a combined medicine) such as an antiemetic, a sleepinducing agent, and an anticonvulsant may be used in combination withthe present compound to inhibit side effects thereof.

The dosage can vary according to each compound and various conditionssuch as patient's disease, age, body weight, sex, symptom, andadministration route. Typically, the present compound is administered toan adult (body weight: 50 kg) at a dose of 0.1 to 1000 mg/day,preferably at a dose of 0.1 to 300 mg/day, which may be administeredonce a day or 2 or 3 times a day. In addition, the present compound maybe administered once in several days to several weeks.

EXAMPLES

Hereinafter, the invention is illustrated in more detail with ReferenceExamples, Examples, and Test Examples, but the invention should not belimited thereto. The compound names as shown in the following ReferenceExamples and Examples do not necessarily follow the IUPAC nomenclaturesystem.

The following abbreviations may be used herein.

THF: tetrahydrofuran

TFA: trifluoroacetic acid

(Boc)₂O: di-tert-butyl dicarbonate

DMF: N,N-dimethylformamide

DIEA: N,N-diisopropylethylamine

EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

EDCI.HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HOBt: 1-hydroxybenzotriazole

HOBt.H₂O: 1-hydroxybenzotriazole monohydrate

Me: methyl

Et: ethyl

Ac: acetyl

Boc: tert-butoxycarbonyl

SEM: 2-(trimethylsilyl)ethoxymethyl

DMAP: N,N-dimethyl-4-aminopyridine

Rt: retention time

LC/MS analysis condition in the compound identification is as follows.

LC/MS measurement:

Detection device: ACQUITY® SQ deteceter (Waters)

HPLC: ACQUITY UPLC® system

Column: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm×30 mm)

Solvent: A solution: 0.06% formic acid/H₂O, B solution: 0.06% formicacid/MeCN

Gradient condition: 0.0-1.3 min Linear gradient from B 2% to 96%

Flow rate: 0.8 mL/min

UV: 220 nm and 254 nm

The compounds of Examples 38 to 41 were identified under the followingLC/MS analysis condition.

LC/MS measurement:

Detection device: detector Perkin-Elmer Sciex API 150EX Massspectrometer (40 eV)

HPLC: Shimadzu LC 10ATVP

Column: Shiseido CAPCELL PAK C18 ACR (S-5 μm, 4.6 mm×50 mm)

Solvent: A solution: 0.035% TFA/MeCN, B solution: 0.05% TFA/H₂O

Gradient condition: 0.0-0.5 min A 10%, 0.5-4.8 min Linear gradient fromA 10% to 99%, 4.8-5.0 min A 99%

Flow rate: 3.5 mL/min

UV: 220 nm and 254 nm

Reference Example 1-1 Methyl1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxylate

To a solution of methyl 4-imidazole-carboxylate (14.0 g) in acetonitrile(200 mL) were added potassium carbonate (19.9 g) and potassium iodide(0.092 g), and then 3,4,5-trifluorobenzyl bromide (14.6 mL) was addeddropwise thereto at room temperature. The mixture was stirred at 70° C.for 6 hours and then cooled to room temperature, and to the reactionmixture was added water, and then the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,filtered, and then concentrated in vacuo. The resulting crude productwas washed with hexane/ethyl acetate (1/2, 60 mL) to give the titlecompound (14.0 g).

LC-MS ([M+H]⁺/Rt (min)): 271.4/0.725

Reference Example 1-21-(3,4,5-Trifluorobenzyl)-1H-imidazole-4-carboxylic acid

To a solution of the compound of Reference Example 1-1 (4.75 g) inmethanol/THF (50 mL/50 mL) was added 2 mol/L aqueous sodium hydroxidesolution (13.2 mL), and the mixture was stirred at 50° C. for 5 hours.The reaction mixture was concentrated in vacuo, and the residue wasdissolved in water, and then aqueous hydrochloric acid solution wasadded thereto to adjust pH to 5. The resulting precipitate was collectedon a filter, washed with water and hexane, and then dried at 50° C. invacuo to give the title compound (4.52 g).

LC-MS ([M+H]⁺/Rt (min)): 257.1/0.513

Reference Example 2 1-(3,4-Difluorobenzyl)-1H-imidazole-4-carboxylicacid

According to the processes of Reference Example 1-1 and ReferenceExample 1-2, the title compound was prepared from 3,4-difluorobenzylbromide.

LC-MS ([M+H]⁺/Rt (min)): 239.1/0.460

Reference Example 3 tert-Butyl7-fluoro-6-({[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]carbonyl}amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of the compound of Reference Example 1-2 (897 mg) in DMF(15 mL) were added tert-butyl6-amino-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (932 mg),EDCI.HCl (805 mg), HOBt (567 mg) and N,N-diisopropylethylamine (1.22mL), and the mixture was stirred at 80° C. for 7 hours. To the reactionmixture was added water and then aqueous sodium hydroxide, and themixture was extracted with chloroform. The organic layer was washed withbrine, dried over magnesium sulfate, filtered, and then concentrated invacuo. The residue was purified by silica gel column chromatography(chloroform/methanol) to give the title compound (1.50 g).

LC-MS ([M+H]⁺/Rt (min)): 505.3/1.137

Reference Examples 4 to 6

According to the process of Reference Example 3, the compounds ofReference Examples 4 to 6 were prepared from the corresponding startingcompounds.

LC-MS: Reference [M + H]⁺/ Example Chemical Structural Formula Rt (min)4

487.6/1.084 5

487.0/1.112 6

488.3/1.006

Reference Example 7 tert-Butyl6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate

To a solution of tert-butyl 6-hydroxy-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate (1.73 g) in pyridine (20 mL) was addedtrifluoromethanesulfonic anhydride (1.28 mL) with ice-cooling, and themixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (hexane/ethyl acetate) to give thetitle compound (1.72 g). LC-MS ([M+H]⁺/Rt (min)): 383.2/1.112

Reference Example 8 tert-Butyl6-bromo-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

To acetic acid (15 mL) was added sodium borohydride (340 mg) at roomtemperature. To the reaction solution was added6-bromo-5-fluoroisoquinoline (1.0 g), and the mixture was stirred atroom temperature for 15 hours. To the reaction solution was added sodiumborohydride (345 mg) at room temperature for 1 hour. The reactionmixture was concentrated in vacuo, and the residue was dissolved in THF(20 mL). Di-tert-butyl dicarbonate (2.04 g) and triethylamine (3.1 mL)were added thereto, and the mixture was stirred at room temperature for2 hours. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate, filtered, and then concentrated in vacuo. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to give the title compound (1.17 g).

LC-MS ([M+H]⁺/Rt (min)): 330.2/1.213

Reference Examples 9 to 10

According to the process of Reference Example 8, the compounds ofReference Examples 9 to 10 were prepared from the corresponding startingcompounds.

LC-MS: Reference [M + H]⁺/ Example Chemical Structural Formula Rt (min)   9

330.1/1.244 10

330.4/1.217

Reference Example 11-14-Nitro-1-[3-(trifluoromethyl)benzyl]-1H-imidazole

4-Nitro-1H-imidazole (35.8 g), 3-trifluoromethylbenzyl bromide (75.7 g),potassium iodide (0.131 g), potassium carbonate (48.1 g) andacetonitrile (270 mL) were mixed, and the mixture was stirred at 80° C.for 5 hours. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate, filtered, and then concentrated invacuo. To the resulting solid was added diisopropyl ether (300 mL), andthe mixture was stirred at room temperature for 1 hour. The resultingprecipitate was collected on a filter, washed with diisopropyl ether,and then dried at 50° C. in vacuo to give the title compound (69.0 g).

LC-MS ([M+H]⁺/Rt (min)): 272.1/0.835

Reference Example 11-21-[3-(Trifluoromethyl)benzyl]-1H-imidazole-4-amine hydrochloride

To a solution of the compound of Reference Example 11-1 (34.0 g) inethyl acetate (330 mL) was added rhodium-activated carbon (5%, 17.0 g),and the mixture was stirred under hydrogen atmosphere at roomtemperature for 14 hours.

The reaction mixture was filtered through Celite®, washed with ethylacetate (50 mL×4), and then to the filtrate was added hydrogen chloride(4 mol/L in ethyl acetate, 38.0 mL). The filtrate was concentrated invacuo, and then to the resulting crude product were added ethyl acetate(200 mL) and hexane (200 mL), and the mixture was stirred at roomtemperature for 10 minutes. The resulting precipitate was collected on afilter and washed with hexane/ethyl acetate (1/1, 20 mL×3), and then theresulting solid was dried at 40° C. in vacuo to give the title compound(31.4 g).

LC-MS ([M+H]⁺/Rt (min)): 242.1/0.548

Reference Example 12 1-(3,4,5-Trifluorobenzyl)-1H-imidazole-4-aminehydrochloride

According to the processes of Reference Examples 11-1 and 11-2, thetitle compound was prepared from 3,4,5-trifluorobenzyl bromide.

LC-MS ([M+H]⁺/Rt (min)): 228.1/0.473

Reference Example 13-1 tert-Butyl6-cyano-8-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of the compound of Reference Example 9 (124 mg) in DMF (1mL) were added tetrakis(triphenylphosphine)palladium (45 mg) and zinccyanide (57 mg), and the mixture was stirred at 120° C. for 8 hours. Thereaction mixture was concentrated in vacuo, and then the residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (48 mg).

LC-MS ([M+H]⁺/Rt (min)): 277.2/1.048

Reference Example 13-2-12-(tert-Butoxycarbonyl)-8-fluoro-1,2,3,4-tetrahydroisoquinoline-6-carboxylicacid

To a solution of the compound of Reference Example 13-1 (2.13 g) in2-propanol (40 mL) were added water (10 mL) and sodium hydroxide (5 g),and the mixture was stirred at 110° C. for 11 hours. The reactionmixture was concentrated in vacuo, and the residue was extracted withsaturated aqueous sodium bicarbonate solution. The aqueous layer wasacidified with sodium hydrogen sulfate and extracted with chloroform.The resulting organic layer was dried over sodium sulfate andconcentrated in vacuo to give the title compound (2.54 g).

LC-MS ([M+H]⁺/Rt (min)): 296.2/0.907

Reference Examples 13-2-2 to 13-2-4

According to the processes of Reference Example 13-1 and 13-2-1, thecompounds of Reference Example 13-2-2 to 13-2-4 were prepared from thecorresponding starting compounds.

LC-MS: Reference [M + H]⁺/ Example Chemical Structural Formula Rt (min)13-2-2

296.2/0.867 13-2-3

296.1/0.864 13-2-4

279.0/0.537

Reference Example 13-3 tert-Butyl8-fluoro-6-{[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]carbamoyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate

According to the process of Reference Example 3, the title compound wasprepared from the compounds of Reference Example 13-2-1 and ReferenceExample 12.

LC-MS ([M+H]⁺/Rt (min)): 505.3/1.084

Reference Examples 14 to 31

According to the process of Reference Example 3, the compounds ofReference Examples 14 to 31 were prepared from the correspondingstarting compounds.

LC-MS: Reference [M + H]⁺/ Example Chemical Structural Formula Rt (min)14

505.3/1.076 15

488.3/1.019 16

501.9/1.048 17

502.0/1.033 18

488.0/1.012 19

488.3/0.955 20

502.2/0.951 21

505.3/1.071 22

519.3/1.098 23

502.3/1.042 24

502.3/1.031 25

507.9/1.077 26

515.3/1.149 27

515.3/0.966 28

487.4/1.014 29

501.4/1.070 30

487.3/1.023 31

529.6/1.147

Reference Example 32-1 Methyl5-[(tert-butoxycarbonyl)amino]-6-chloro-nicotinate

To a solution of methyl 5-amino-6-chloro-nicotinate (325 mg) in THF (10mL) were added di-tert-butyl dicarbonate (760 mg) and DMAP (11 mg), andthe mixture was stirred at room temperature for 15.5 hours.Additionally, di-tert-butyl dicarbonate (38 mg) was added thereto, andthe mixture was stirred at 60° C. for 45 minutes. The mixture was cooledto room temperature, and the solvent therein was removed. To the residuewere added methanol (5 mL) and potassium carbonate (481 mg), and themixture was stirred at room temperature for 2.5 hours. Saturated aqueousammonium chloride solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered, and then concentrated invacuo. The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound (321 mg).

LC-MS ([M+H]⁺/Rt (min)): 287.1/0.985

Reference Example 32-2 Methyl5-[(tert-butoxycarbonyl)amino]-6-ethenyl-nicotinate

To a solution of the compound of Reference Example 32-1 (321 mg) in amixture of 1,2-dimethoxyethane (9 mL)/water (0.9 mL) were added pinacolvinylboronate (0.575 mL), tetrakis(triphenylphosphine)palladium (129 mg)and potassium carbonate (465 mg), and the mixture was stirred undermicrowave irradiation at 120° C. for 1 hour. The mixture was cooled toroom temperature, and to the reaction mixture was added water, and thenthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, dried over sodium sulfate, filtered, and thenconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (207mg).

LC-MS ([M+H]⁺/Rt (min)): 279.5/0.885

Reference Example 32-3 Methyl5-[(tert-butoxycarbonyl)amino]-6-formyl-nicotinate

To a solution of the compound of Reference Example 32-2 (207 mg) in amixture of acetone (8 mL)/water (4 mL) were added sodium periodate (659mg) and osmium tetraoxide (2.5 wt % in tert-butanol, 0.71 mL), and themixture was stirred at room temperature for 3 hours. To the reactionmixture were added saturated aqueous sodium thiosulfate solution andwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, dried over sodium sulfate, filtered, andthen concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate) to give the title compound(110 mg).

LC-MS ([M+H]⁺/Rt (min)): 281.2/1.037

Reference Example 32-4 Methyl5-[(tert-butoxycarbonyl)amino]-6-(hydroxymethyl)-nicotinate

To a solution of the compound of Reference Example 32-3 (110 mg) inmethanol was added sodium borohydride, and the mixture was stirred atroom temperature for 1 hour. To the reaction mixture were addedsaturated aqueous ammonium chloride solution and water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, dried over sodium sulfate, filtered, and then concentrated invacuo to give the title compound (111 mg).

LC-MS ([M+H]⁺/Rt (min)): 282.8/0.761

Reference Example 32-52-Oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazine-7-carboxylic acid

To a solution of the compound of Reference Example 32-4 (111 mg) in THF(2 mL)/methanol (4 mL) was added 2 mol/L aqueous sodium hydroxidesolution (0.39 mL), and the mixture was stirred at room temperature for16 hours. To the reaction mixture was added 2 mol/L hydrochloric acid(0.25 mL) to adjust pH to 7. The reaction mixture was concentrated invacuo to give the title compound (76 mg).

LC-MS ([M+H]⁺/Rt (min)): 195.1/0.325

Reference Example 33

According to the process of Reference Example 3, the compound ofReference Example 33 was prepared from the corresponding startingcompound.

LC-MS: Reference [M + H]⁺/ Example Chemical Structural Formula Rt (min)33

470.3/0.976

Reference Example 34

According to the process of Reference Example 11-1, the compound ofReference Example 34 was prepared from the corresponding startingcompound.

LC-MS: Reference [M + H]⁺/ Example Chemical Structural Formula Rt (min)34

238.1/0.776

Reference Example 35

According to the process of Reference Example 11-2, the compound ofReference Example 35 was prepared from the compound of Reference Example34.

LC-MS: Reference [M + H]⁺/ Example Chemical Structural Formula Rt (min)35

208.1/0.460

Reference Examples 36 to 38

According to the process of Reference Example 3, the compounds ofReference Examples 36 to 38 were prepared from the compound of ReferenceExample 35 and the corresponding starting compounds.

LC-MS: Reference [M + H]⁺/ Example Chemical Structural Formula Rt (min)36

467.4/1.033 37

468.4/0.940 38

468.4/1.020

Reference Example 39-1 3-Aminopyridine-4-carboaldehyde

A solution of (3-aminopyridin-4-yl)-methanol (10.4 g) and manganesedioxide (50.3 g) in chloroform (100 mL) was stirred at room temperaturefor 18 hours. The reaction solution was filtered through Celite andconcentrated to give the title compound (10.1 g).

LC-MS ([M+H]⁺/Rt (min)): 123.0/0.218

Reference Example 39-2 Ethyl 1,7-naphthyridine-3-carboxylatehydrochloride

To a solution of the compound of Reference Example 39-1 (10.1 g) andethyl 3-ethoxyacrylate (13.8 mL) in chloroform (100 mL) was added TFA(63.9 mL) with ice-cooling, and the mixture was stirred for 1 hour withheating under reflux. The reaction solution was concentrated, and theresidue was dissolved in ethyl acetate, washed with saturated aqueoussodium bicarbonate solution and brine, dried over anhydrous sodiumsulfate, filtered, and then concentrated in vacuo. The resulting crudeproduct was dissolved in ethyl acetate (350 mL), and then 4 mol/Lhydrochloric acid-ethyl acetate solution (42 mL) was added thereto, andthe mixture was stirred for 1 hour. The resulting solid was filtered togive the title compound (16.8 g).

LC-MS ([M+H]⁺/Rt (min)): 203.1/0.619

Reference Example 39-3

Ethyl 7,8-dihydro-1,7-naphthyridine-3-carboxylate

To a solution of the compound of Reference Example 39-2 (3.13 g) inmethanol (60 mL) was added sodium borohydride (1.49 g) with ice-cooling,and the mixture was stirred at room temperature for 30 minutes.Additionally, to the reaction solution was added sodium borohydride (0.8g) with ice-cooling, and the mixture was stirred for 30 minutes. Thereaction solution was concentrated, and then the residue was dissolvedin ethyl acetate, washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated to give the title compound (2.68 g).

LC-MS ([M+H]⁺/Rt (min)): 205.1/0.420

Reference Example 39-4 7-tert-Butyl 3-ethyl5,8-dihydro-1,7-naphthyridine-3,7(6H)-dicarboxylate

A solution of the compound of Reference Example 39-3 (2.68 g), Boc₂O(12.6 g) and palladium/carbon (1.6 g) in THF (100 mL) was stirred underhydrogen atmosphere at room temperature for 18 hours. The reactionsolution was filtered through Celite® and concentrated. The resultingresidue was purified by silica gel column chromatography to give thetitle compound (1.51 g).

LC-MS ([M+H]⁺/Rt (min)): 307.47/0.967

Reference Example 39-5 Sodium7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylate

To a solution of the compound of Reference Example 39-4 (1.51 g) in THF(20 mL) were added water (5 mL) and 5 mol/L aqueous sodium hydroxidesolution (1.5 mL) with ice-cooling, and the mixture was stirred at roomtemperature for 7 hours. The reaction solution was washed with diethylether, and then the aqueous phase was concentrated to give the titlecompound (1.51 g).

LC-MS ([M-H]⁺/Rt (min)): 279.2/0.707

Reference Example 40-14-Nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole

A solution of 4-nitroimidazole in DMF (50 mL) was added dropwise to asolution of sodium hydride (10.3 g) in DMF (50 mL) with ice-cooling, andthe mixture was stirred with ice-cooling for 30 minutes.2-(Trimethylsilyl)ethoxymethyl chloride (17.5 mL) was added dropwisethereto with ice-cooling, and the mixture was stirred at roomtemperature for 1 hour. To the reaction solution were added methanol (30mL) and ice, and the aqueous layer was extracted with hexane/ethylacetate=1/1. The organic phase was dried over anhydrous magnesiumsulfate, filtered, and then concentrated in vacuo. The resulting crudeproduct was purified by silica gel column chromatography (hexane/ethylacetate) to give the title compound (19.4 g).

LC-MS ([M+H]⁺/Rt (min)): 244.1/0.929

Reference Example 40-2 tert-Butyl6-[(1-{([2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl)carbamoyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate

A solution of the compound of Reference Example 40-1 (3.01 g) andpalladium/carbon (1.57 g) in ethyl acetate (30 mL) was stirred underhydrogen atmosphere at room temperature for 6 hours. The reactionsolution was filtered through Celite®. To the resulting filtrate wereadded WSC (2.48 g),2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid(2.29 g) and DIEA (4.33 mL), and the mixture was stirred at roomtemperature for 18 hours. The reaction solution was washed withsaturated aqueous sodium bicarbonate solution and brine, dried oversodium hydrogen sulfate, filtered, and then concentrated. The resultingresidue was purified by silica gel column chromatography (hexane/ethylacetate) to give the title compound (2.95 g).

LC-MS ([M+H]⁺/Rt (min)): 473.4/1.106

Reference Example 40-3 tert-Butyl6-{[1-(tert-butoxycarbonyl)-1H-imidazol-4-yl]carbamoyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate

A solution of the compound of Reference Example 40-2 (1.08 g) in 4 mol/Ldioxane hydrochloride (50 mL) was stirred for 8 hours with heating underreflux. The reaction solution was concentrated, and then to a solutionof the resulting residue in tetrahydrofuran (50 mL) were added (Boc)₂O(2.11 g) and triethylamine (1.6 mL), and the mixture was stirred at roomtemperature for 24 hours. The reaction solution was concentrated, andthen the resulting crude product was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (0.35g).

LC-MS ([M+H]⁺/Rt (min)): 443.4/1.085

Reference Example 40-4 tert-Butyl6-(1H-imidazol-4-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of the compound of Reference Example 40-3 (0.35 g) intetrahydrofuran (10 mL) was added 5 mol/L aqueous sodium hydroxidesolution (0.5 mL) with ice-cooling, and the mixture was stirred at roomtemperature for 24 hours. The reaction solution was concentrated, andthen the resulting residue was dissolved in ethyl acetate and washedwith water and brine. The resulting organic phase was dried overanhydrous magnesium sulfate, filtered, and then concentrated in vacuo togive the title compound (0.26 g).

LC-MS ([M+H]⁺/Rt (min)): 343.2/0.697

Reference Example 40-5 tert-Butyl6-[(1-benzyl-1H-imidazol-4-yl)carbamoyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of the compound of Reference Example 40-4 (0.07 g) in DMF(1 mL) were added sodium carbonate (0.03 g) and benzyl bromide (0.04 g),and the mixture was stirred at 100° C. for 4 hours. The reactionsolution was concentrated, and then the resulting crude product waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (0.03 g).

LC-MS ([M+H]⁺/Rt (min)): 433.4/0.903

Reference Examples 41 to 62

According to the process of Reference Example 40-5, the compounds ofReference Examples 41 to 62 were prepared from the compound of ReferenceExample 40-4 and the corresponding starting compounds.

LC-MS: Reference [M + H]⁺/ Example Q¹—W¹— Rt (min)   41

451.3/0.981 42

469.4/1.014 43

469.4/1.019 44

517.4/1.096 45

447.3/1.020 46

451.3/0.988 47

463.3/1.001 48

451.3/1.013 49

447.3/1.057 50

447.1/1.093 51

501.4/1.128 52

501.4/1.139 53

463.4/1.019 54

439.4/0.960 55

453.4/1.021 56

467.3/1.006 57

458.3/0.896 58

525.4/1.094 59

485.3/1.028 60

485.3/1.040 61

519.3/1.049 62

535.3/1.200

Reference Example 63-1 tert-Butyl3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl)carbamoyl]-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate

According to the process of Reference Example 40-2, the title compoundwas prepared from the compounds of Reference Examples 39-5 and 40-1.

LC-MS ([M+H]⁺/Rt (min)): 474.4/1.012

Reference Example 63-2 tert-Butyl3-{[1-(tert-butoxycarbonyl)-1H-imidazol-4-yl]carbamoyl}-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate

According to the process of Reference Example 40-3, the title compoundwas prepared from the compound of Reference Example 63-1.

Reference Example 63-3 tert-Butyl3-(1H-imidazol-4-ylcarbamoyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate

According to the process of Reference Example 40-4, the title compoundwas prepared from the compound of Reference Example 63-2.

LC-MS ([M+H]⁺/Rt (min)): 344.2/0.572

Reference Examples 64 to 88

According to the process of Reference Example 40-5, the compounds ofReference Examples 64 to 88 were prepared from the compound of ReferenceExample 63-3 and the corresponding starting compounds.

LC-MS: Reference [M + H]⁺/ Example Q¹—W¹— Rt (min)   64

452.4/0.851 65

470.3/0.890 66

470.3/0.897 67

518.3/0.987 68

526.4/1.038 69

486.3/0.951 70

466.3/0.953 71

520.3/0.971 72

536.3/1.022 73

440.4/0.931 74

454.4/1.010 75

435.4/0.635 76

464.3/0.863 77

434.3/0.850 78

448.3/0.895 79

452.4/0.866 80

502.3/0.960 81

459.3/0.819 82

502.3/0.969 83

468.3/0.933 84

484.4./0.966 85

549.4/0.951 86

448.3/0.909 87

462.4./0.906 88

552.3/1.067

Reference Example 89-1 Methyl (2E)-3-(isoquinolin-6-yl)prop-2-enoate

To a solution of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (0.98 g) inDMF (10 mL) were added palladium acetate (0.09 g), copper acetate (1.40g), lithium acetate dihydrate (0.78 g) and methyl acrylate (334 μL), andthe mixture was stirred at 100° C. for 4 hours. The reaction solutionwas concentrated, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (0.46g).

LC-MS ([M+H]⁺/Rt (min)): 214.1/0.475

Reference Example 89-2 tert-Butyl6-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of the compound of Reference Example 89-1 (0.46 g) inacetic acid (1 mL) was added sodium borohydride (0.10 g), and themixture was stirred at room temperature for 30 minutes. The reactionsolution was basified with saturated aqueous sodium hydrogen carbonatesolution, THF (10 mL) and Boc₂O (0.49 g) were added thereto, and thenthe mixture was stirred at room temperature for 16 hours. The reactionsolution was diluted with ethyl acetate, washed with water and brine,dried over anhydrous sodium sulfate, filtered, and then concentrated.The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound (0.03 g).

LC-MS ([M+H]⁺/Rt (min)): 318.2/1.103

Reference Example 89-3(2E)-3-[2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]prop-2-enoicacid

To a solution of the compound of Reference Example 89-2 (0.03 g) in THF(4 mL) and water (1 mL) was added lithium hydroxide (0.01 g) withice-cooling, and the mixture was stirred at room temperature for 13hours. The reaction solution was diluted with saturated aqueous sodiumhydrogen carbonate solution and washed with diethyl ether. The resultingaqueous phase was acidified with sodium hydrogen sulfate and thenextracted with chloroform. The organic layer was dried over anhydroussodium sulfate and then concentrated to give the title compound (0.03g).

LC-MS ([M-H]⁻/Rt (min)): 302.5/0.916

Reference Example 89-4 tert-Butyl6-[(1E)-3-oxo-3-{[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]amino}prop-1-en-1-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate

According to the process of Reference Example 3, the title compound wasprepared from the corresponding starting compound.

LC-MS ([M+H]⁺/Rt (min)): 513.0/1.084

Reference Examples 90 to 98

According to the process of Reference Example 40-5, the compounds ofReference Examples 90 to 98 were prepared from the compound of ReferenceExample 63-3 and the corresponding starting compounds.

LC-MS: Reference [M + H]⁺/Rt Example Q¹—W¹— (min) 90

493.3/0.879 91

512.3/0.779 92

477.4/1.031 93

465.4/0.902 94

479.3/0.934 95

442.4/0.858 96

479.3/0.867 97

453.3/1.060 98

448.4/1.200

Example 1N-(7-Fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamide

To a solution of the compound of Reference Example 3 (1.5 g) in methanol(40 mL) was added 4 mol/L dioxane hydrochloride (2.97 mL), and themixture was stirred at room temperature overnight. The reaction mixturewas concentrated in vacuo, and then water and 2 mol/L aqueous sodiumhydroxide solution were added thereto. The resulting precipitate wascollected on a filter, washed with water and hexane/ethyl acetate (2/1),and dried in vacuo to give the title compound (0.89 g).

LC-MS ([M+H]⁺/Rt (min)): 405.2/0.665

¹H-NMR (400 MHz, DMSO-d₆) :δ 9.27 (1H, s), 7.96-7.93 (2H, m), 7.69 (1H,d, J=8.0 Hz), 7.43-7.34 (2H, m), 6.91 (1H, d, J=11.6 Hz), 5.23 (2H, s),3.75 (2H, s), 2.90-2.86 (2H, m), 2.62-2.57 (2H, m).

Examples 2 to 3

According to the process of Example 1, the compounds of Examples 2 to 3were prepared from the corresponding compounds of each ReferenceExample.

Example Chemical Structural Formula Instrumental Analysis Data 2

¹H-NMR (400 MHz, DMSO-d₆): 9.28 (1H, s), 7.96-7.93 (2H, m), 7.71 (1H, d,J = 7.6 Hz), 7.53-7.42 (2H, m), 7.22-7.18 (1H, m), 6.93 (1H, d, J = 10.8Hz), 5.24 (2H, s), 3.78 (2H, s), 2.93-2.89 (2H, m), 2.65-2.59 (2H, m).LC-MS: [M + H]⁺/Rt (min): 387.0/0.660 3

¹H-NMR (400 MHz, DMSO-d₆): 9.30 (1H, s), 8.02 (1H, s), 7.97 (1H, s),7.96 (1H, s), 7.88 (1H, s), 7.43-7.37 (2H, m), 5.23 (2H, s), 3.78 (2H,s), 2.92-2.88 (2H, m), 2.71-2.66 (2H, m). LC-MS: [M + H]⁺/Rt (min):388.2/0.601

Example 4N-(1,2,3,4-Tetrahydroisoquinolin-6-yl)-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamidedihydrochloride

To a solution of the compound of Reference Example 4 (75 mg) in methanol(5 mL) was 4 mol/L dioxane hydrochloride (0.12 mL), and the mixture wasstirred at 80° C. The resulting precipitate was collected on a filter,washed with diisopropyl ether, and then dried in vacuo to give the titlecompound (35.8 mg).

LC-MS ([M+H]⁻/Rt (min)): 387.2/0.615

Examples 5 to 15

According to the process of Example 4, the compounds of Examples 5 to 15were prepared from the corresponding compounds of each ReferenceExample.

Example Chemical Structural Formula Instrumental Analysis Data  5

¹H-NMR (400 MHz, CD₃OD): 8.94 (1H, d, J = 1.6 Hz), 7.78 (1H, s), 7.65(1H, d, J = 9.2 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.33-7.30 (2H, m), 5.44(2H, s), 4.46 (2H, s), 3.56 (2H, t, J = 6.4 Hz), 3.24 (2H, t, J = 6.0Hz). LC-MS ([M + H]⁺/Rt (min)): 405.2/0.645  6

¹H-NMR (400 MHz, CD₃OD): 8.89 (1H, d, J = 2.0 Hz), 7.87 (2H, m), 7.55(1H, d, J = 2.0 Hz), 7.42 (1H, d, J = 8.4 Hz), 7.33-7.27 (2H, m), 5.43(2H, s), 4.46 (2H, s), 3.56 (2H, t, J = 6.4 Hz), 3.22 (2H, t, J = 6.4Hz). LC-MS ([M + H]⁺/Rt (min)): 387.2/0.635  7

¹H-NMR (400 MHz, CD₃OD): 7.77 (1H, d, J = 6.8 Hz), 7.58 (1H, s),7.27-7.22 (4H, m), 5.37 (2H, s), 4.44 (2H, s), 3.54 (2H, t, J = 6.4 Hz),3.16 (2H, t, J = 6.4 Hz). LC-MS([M + 2H]²⁺/Rt (min)): 203.1/0.620  8

¹H-NMR (400 MHz, CD₃OD): 8.90 (1H, d, J = 1.6 Hz), 8.61 (1H, s), 8.17(1H, s), 7.65 (1H, d, J = 1.6 Hz), 7.35-7.28 (2H, m), 5.43 (2H, s), 4.54(2H, s), 3.58 (2H, t, J = 6.4 Hz), 3.26 (2H, t, J = 6.4 Hz). LC-MS ([M +H]⁺/Rt (min)): 388.2/0.554  9

¹H-NMR (400 MHz, CD₃OD): 8.94 (1H, s), 8.60 (1H, s), 8.12 (1H, s), 7.82(1H, s), 7.76-7.65 (4H, m), 5.55 (2H, s), 4.53 (2H, s), 3.58 (2H, t, J =5.2 Hz), 3.26 (2H, t, J = 6.4 Hz) LC-MS [M + 2H]²⁺/Rt (min)):201.7/0.659 10

¹H-NMR (400 MHz, CD₃OD): 8.84 (1H, s), 8.12 (1H, d, J = 8.4 Hz), 7.91(1H, d, J = 8.4 Hz), 7.81 (1H, s), 7.75-7.64 (4H, m), 5.54 (2H, s), 4.53(2H, s), 3.69 (2H, t, J = 6.4 Hz), 3.36 (2H, t, J = 6.4 Hz). LC-MS ([M +2H]²⁺/Rt (min)): 201.7/0.620 11

¹H-NMR (400 MHz, CD₃OD): 8.80 (1H, d, J = 1.6 Hz), 8.13 (1H, d, J = 8.0Hz), 7.92 (1H, d, J = 8.4 Hz), 7.67 (1H, d, J = 2.0 Hz), 7.33-7.26 (2H,m), 5.42 (2H, s), 4.54 (2H, s), 3.70 (2H, t, J = 6.4 Hz), 3.37 (2H, t, J= 6.4 H). LC-MS: [M + 2H]²⁺/Rt (min): 194.7/0.636 12

¹H-NMR (400 MHz, CD₃OD): 9.03 (1H, s), 9.00 (1H, s), 8.31 (1H, s), 7.61(1H, s), 7.32 (2H, t, J = 7.2 Hz), 5.44 (2H, s), 4.50 (2H, s), 3.61 (2H,t, J = 6.4 Hz), 3.26 (2H, t, J = 6.4 Hz). LC-MS: [M + 2H]²⁺/Rt (min):194.7/0.624 13

¹H-NMR (400 MHz, CD₃OD): 9.00 (1H, d, J = 2.4 Hz), 8.76 (1H, s), 8.26(1H, d, J = 1.6 Hz), 7.78-7.57 (4H, m), 7.56 (1H, d, J = 0.8 Hz), 5.51(2H, s), 4.48 (2H, s), 3.60 (2H, t, J = 6.4 Hz), 3.24 (2H, t, J = 6.4Hz). LC-MS: [M + H]⁺/Rt (min): 402.3/0.590 14

¹H-NMR (400 MHz, CD₃OD): 8.72 (1H, s), 7.77 (1H, t, J = 7.6 Hz), 7.59(1H, d, J = 1.2 Hz), 7.29-7.24 (3H, m), 5.39 (2H, s), 4.47 (2H, s), 3.58(2H, t, J = 6.4 Hz), 3.15 (2H, t, J = 6.4 Hz). LC-MS: [M + 2H]²⁺/Rt(min): 203.1/0.650 15

¹H-NMR (400 MHz, CD₃OD): 8.83 (1H, s), 7.80-7.61 (5H, m), 7.59 (1H, d, J= 1. 2 Hz), 7.24 (1H, d, J = 7.6 Hz), 5.52 (2H, s), 4.47 (2H, s), 3.58(2H, t, J = 6.4 Hz), 3.15 (2H, t, J = 6.4 Hz). LC-MS: [M + 2H]²⁺/Rt(min): 210.1/0.708

Examples 16 to 17

According to the process of Reference Example 3, the correspondingintermediates of Examples 16 to 17 were synthesized, and then thecompounds of Examples 16 to 17 were prepared from the correspondingintermediates according to the process of Example 4 withoutpurification.

Example Chemical Structural Formula Instrumental Analysis Data 16

LC-MS: [M + 2H]²⁺/Rt (min): 204.2/0.632 17

LC-MS: [M + 2H]²⁺/Rt (min): 204.2/0.634

Examples 18 to 22

According to the process of Example 4, the compounds of Examples 18 to22 were prepared from the corresponding compounds of each ReferenceExample.

Example Chemical Structural Formula Instrumental Analysis Data 18

LC-MS: [M + H]⁺/Rt (min): 401.3/0.588 19

LC-MS: [M + 2H]²⁺/Rt (min): 201.2/0.663 20

LC-MS: [M + H]⁺/Rt (min): 408.2/0.603 21

¹H-NMR (400 MHz, CD₃OD): 8.93 (1H, s), 7.91-7.88 (2H, m), 7.78-7.60 (4H,m), 7.42 (1H, d, J = 8.0 Hz), 5.57 (2H, s), 4.47 (2H, s), 3.56 (2H, t, J= 6.4 Hz), 3.22 (2H, t, J = 6.4 Hz), 2.21 (3H, d, J = 1.2 Hz). LC-MS:[M + 2H]²⁺/Rt (min): 208.2/0.668 22

¹H-NMR (400 MHz, CD₃OD): 7.88-7.85 (2H, m), 7.75-7.73 (2H, m), 7.68-7.60(2H, m), 7.42-7.38 (2H, m), 5.49 (2H, s), 4.46 (2H, s), 3.55 (2H, t, J =6.4 Hz), 3.21 (2H, t, J = 6.0 Hz), 2.68 (3H, d, J = 2.4 Hz). LC-MS: [M +2H]²⁺/Rt (min): 208.2/0.583

Examples 23 to 24

According to the process of Reference Example 3, the compounds ofExamples 23 to 24 were prepared from the corresponding compounds of eachReference Example and the corresponding starting compounds.

LC-MS: Example Chemical Structural Formula [M + H]⁺/Rt (min) 23

401.9/0.844 24

418.2/0.711

Example 25N-[1-(3,4,5-Trifluorobenzyl)-1H-imidazol-4-yl]-(1,2,3,4-tetrahydroisoquinoline-6-carboxamideditrifluoroacetate

To a solution of the compound of Reference Example 28 (103 mg) inchloroform (9 mL) was added trifluoroacetic acid (1 mL), and the mixturewas stirred at room temperature for 5 hours. The reaction mixture wasconcentrated in vacua, to the residue was added a mixed solvent ofhexane-ethyl acetate, and the mixture was stirred at room temperaturefor 1 hour. The resulting precipitate was collected on a filter anddried in vacuo to give the title compound (91 mg).

LC-MS ([M+2H]²⁻/Rt (min)): 194.1/0.580

¹H-NMR (400 MHz, CDCl :δ 7.94 (1H, d, J=1.6 Hz), 7.85-7.83 (2H, m), 7.47(d, 1H, J=2.0 Hz), 7.38 (d, 1H, J=8.4 Hz), 7.14 (dd, 2H, J=8.4, 6.8 Hz),5.26 (s, 2H), 4.44 (s, 2H), 3.55 (t, 2H, J=6.4 Hz), 3.20 (t, 2H, J=6.4Hz).

Examples 26 to 29

According to the process of Example 25, the compounds of Examples 26 to29 were prepared from the corresponding compounds of each ReferenceExample.

Example Chemical Structural Formula Instrumental Analysis Data 26

LC-MS: [M + H]⁺/Rt (min): 401.3/0.588 27

LC-MS: [M + H]⁺/Rt (min): 401.3/0.899 28

LC-MS: [M + 2H]²⁺/Rt (min): 194.5/0.601 29

LC-MS: [M + H]⁺/Rt (min): 429.3/0.706

Example 302-Methyl-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide

To a solution of the compound of Example 26 (33 mg) in THF (1 mL) wereadded aqueous formaldehyde solution (1 mL) and sodiumtriacetoxyborohydride (23 mg), and the mixture was stirred at roomtemperature for 19 hours. The reaction mixture was concentrated invacuo, and the residue was dissolved in chloroform, washed withsaturated aqueous sodium bicarbonate solution and brine, dried overanhydrous sodium sulfate, filtered, and then concentrated in vacuo. Theresulting residue was purified by silica gel column chromatography(chloroform/methanol) to give the title compound (12 mg).

LC-MS ([M+H]⁺/Rt (min)): 415.6/0.575

Example 31N-[1-(3,4,5-Trifluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide

A suspension of the compound of Example 25 (80 mg) in ethyl acetate (100mL) was washed with saturated aqueous sodium bicarbonate solution, andthe resulting organic layer was dried over anhydrous sodium sulfate andthen concentrated in vacuo to give the title compound (50 mg).

LC-MS ([M+2H]²⁺/Rt (min)): 194.1/0.580

Examples 32 to 34

According to the process of Example 31, the compounds of Examples 32 to34 were prepared from the corresponding compounds of each ReferenceExample.

Example Chemical Structural Formula Instrumental Analysis Data 32

LC-MS: [M + H]⁺/Rt (min): 429.3/0.706 33

LC-MS: [M + 2H]²⁺/Rt (min): 194.5/0.601 34

LC-MS: [M + 2H]²⁺/Rt (min): 201.2/0.617

Example 351-(3,4-Difluorobenzyl)-N-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-1H-imidazole-4-carboxamide

To a solution of the compound of Reference Example 33 (111 mg) inmethanol (4 mL) was added 4 mol/L dioxane hydrochloride (1.66 mL), andthe mixture was stirred at room temperature overnight. The mixture wasthen stirred at 50° C. for 6 hours. The reaction mixture wasconcentrated in vacuo, and then water and 2 mol/L aqueous sodiumhydroxide solution were added thereto. The resulting precipitate wascollected on a filter and washed with water and hexane/ethyl acetate(2/1). The resulting crude product was purified by amino silica gelcolumn chromatography (chloroform/methanol) to give the title compound(29.5 mg).

LC-MS ([M+H]^(|)/Rt (min)): 370.2/0.618

H-NMR (400 MHz, DMSO-d₆) : 9.31 (1H, s), 8.02-7.97 (3H, m), 7.90 (1H,s), 7.57-7.41 (2H, m), 7.25-7.21 (2H, m), 5.26 (2H, s), 3.79 (2H, s),2.93-2.89 (2H, m), 2.72-2.68 (2H, m).

Examples 36 to 42

According to the process of Reference Example 3, the compounds ofExamples 36 to 42 were prepared from the corresponding compounds of eachReference Example.

LC-MS: Example Chemical Structural Formula [M + H]⁺/Rt (min) 36

416.3/0.754 37

401.2/0.715 38

382.1/3.23 39

396.1/3.21 40

418.0/3.58 41

380.2/3.23 42

404.9/0.781

Examples 43 to 70

According to the process of Example 4, the compounds of Examples 43 to70 were prepared from the corresponding compounds of each ReferenceExample.

LC-MS: Example Chemical Structural Formula [M + H]⁺/Rt (min) 43

368.2/0.563 44

368.2/0.577 45

367.2/0.569

LC-MS: Reference [M + H]⁺/Rt Example Q¹—W¹— (min) 46

352.2/0.491 47

370.3/0.524 48

379.3/0.523 49

418.3/0.641 50

426.3/0.664 51

386.2/0.584 52

386.2/0.580 53

420.3/0.616 54

436.2/0.661 55

340.3/0.520 56

354.4/0.617 57

335.3/0.280 58

364.4/0.498 59

334.3/0.466 60

348.4/0.534 61

352.3/0.487 62

402.4/0.595 63

359.3/0.443 64

402.3/0.610 65

368.3/0.567 66

384.4/0.618 67

349.3/0.324 68

348.3/0.536 69

362.3/0.531 70

452.3/0.687

Examples 71 to 93

According to the process of Example 1, the compounds of Examples 71 to93 were prepared from the corresponding compounds of each ReferenceExample (Example).

LC-MS: [M + H]⁺/Rt Example Q¹—W¹— (min) 71

333.2/0.558 72

351.3/0.581 73

369.2/0.633 74

369.2/0.626 75

417.3/0.744 76

347.3/0.626 77

351.2/0.593 78

363.3/0.660 79

351.2/0.668 80

347.3/0.739 81

347.2/0.551 82

401.3/0.609 83

401.3/0.627 84

363.2/0.494 85

339.2/0.568 86

353.3/0.633 87

367.1/0.562 88

358.4/0.444 89

425.3/0.691 90

385.3/0.587 91

385.2/0.590 92

419.3/0.629 93

435.2/0.663

Examples 94 to 107

According to process of Example 1 or 4, the compounds of Examples 94 to107 were prepared from the corresponding compounds of each ReferenceExample.

Example Chemical Structural Formula Instrumental Analysis Data  94

LC-MS ([M + 2H]²⁺/ Rt (min)): 197.3/0.510  95

LC-MS ([M + 2H]²⁺/ Rt (min)): 193.2/0.575  96

LC-MS ([M + 2H]²⁺/ Rt (min)): 246.1/0.669  97

LC-MS ([M + 2H]²⁺/ Rt (min)): 208.2/0.656  98

LC-MS ([M + 2H]²⁺/ Rt (min)): 216.3/0.638  99

LC-MS ([M + 2H]²⁺/ Rt (min)): 210.2/0.658 100

LC-MS ([M + 2H]²⁺/ Rt (min)): 226.2/0.740 101

LC-MS ([M + H]⁺/ Rt (min)): 401.2/0.656 102

LC-MS ([M + 2H]²⁺/ Rt (min)): 201.2/0.630 103

LC-MS ([M + 2H]²⁺/ Rt (min)): 192.2/0.607 104

LC-MS ([M + 2H]²⁺/ Rt (min)): 196.2/0.574 105

LC-MS ([M + H]⁺/ Rt (min)): 376.3/0.426 106

LC-MS ([M + H]⁺/ Rt (min)): 334.2/0.296 107

LC-MS ([M + H]⁺/ Rt (min)): 349.2/0.416

Example 1082-Acetyl-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamidetrifluoroacetate

To a solution of the compound of Example 26 (0.03 g) in THF (1 mL) wereadded pyridine (25 μL) and acetic anhydride (12 μL), and the mixture wasstirred at room temperature for 3 hours. The reaction solution wasconcentrated, and then the residue was purified by reverse-phase HPLC(mobile phase: 0.05% TFA/water and 0.035% TFA/acetonitrile) to give thetitle compound (0.02 g).

LC-MS ([M+H]⁺/Rt (min)): 443.3/0.825

Example 109N-{1-[3-(Trifluoromethyl)benzyl]-1H-imidazol-4-yl}-3′,4′-dihydro-1′H-spiro[1,3-dioxolane-2,2′-naphthalene]-6′-carboxamide

According to the process of Reference Example 3, the title compound wasprepared from the compound of Reference Example 11-2 and the compounddescribed in U.S. Pat. No. 5,786,356.

LC-MS ([M+H]⁺/Rt (min)): 458.4/0.870

Example 1106-Oxo-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydronaphthalene-2-carboxamide

A solution of the compound of Example 109 (0.20 g) in a mixed solvent of4 mol/L dioxane hydrochloride (4 mL) and water (1 mL) was stirred atroom temperature for 20 hours. The reaction solution was diluted withethyl acetate, and then washed with saturated aqueous sodium hydrogencarbonate and brine. The organic phase was dried over anhydrous sodiumsulfate, filtered, and then concentrated in vacuo. The resulting residuewas purified by silica gel column chromatography (chloroform/methanol)to give the title compound (0.15 g).

LC-MS ([M+H]⁺/Rt (min)): 414.2/0.805

Example 1116-Hydroxy-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydronaphthalene-2-carboxamide

To a solution of the compound of Example 110 (0.06 g) in methanol wasadded sodium borohydride (0.01 g) with ice-cooling, and then the mixturewas stirred at room temperature for 1 hour. The reaction solution wasdiluted with ethyl acetate and then washed with water and brine. Theorganic phase was dried over anhydrous sodium sulfate, filtered, andthen concentrated in vacuo. The resulting residue was purified by silicagel column chromatography (chloroform/methanol) to give the titlecompound (0.06 g).

LC-MS ([M+H]⁺/Rt (min)): 416.3/0.754

Examples 112 to 121

According to the process of Example 4, the compounds of Examples 112 to121 were prepared from the corresponding compounds of each ReferenceExample.

Example Chemical Structural Formula Instrumental Analysis Data 112

LC-MS ([M + 2H]²⁺/Rt (min)): 207.2/0.649

LC-MS: Reference [M + H]⁺/Rt Example Q¹—W¹— (min) 113

392.3/0.562 114

412.3/0.472 115

477.4/1.031 116

364.3/0.572 117

378.3/0.579 118

342.3/0.430 119

378.3/0.517 120

352.3/0.615 121

348.3/0.647

Test Example 1 Test for Inhibiting Sphere-Forming Ability of CancerCells

The reliable methods established for measuring the self-renewal abilityof cells which is one of the CSC's properties include a method formeasuring the sphere-forming ability of cancer cells in non-adherentcondition in the absence of serum (Cancer Res 65, 5506-5511 (2005)).HCT-116 cells were available from the American Type Culture Collection(ATCC). HCT-116 cells were cultured at 37° C. and 5% CO₂ using theMcCoy's 5a medium containing 10% fetal bovine serum (FBS) and 1%penicillin/streptomycin. HCT-116 cells were seeded in a 384 Well BlackClear Bottom Ultra-Low Attachment Microplate (Corning Cat. No.3827) inan amount of 350-800 cells/well using the DMEM/F12 medium containing 2%B27 supplement (GIBCO), 20 ng/mL epidermal growth factor (EGF)(peprotech), 10 ng/mL basic fibroblast growth factor (bFGF) (peprotech),5 μg/mL insulin (Sigma), and 1% penicillin/streptomycin. The testcompounds were added into each well to adjust the final concentration ofDMSO to 0.1%, and the cells were cultured for 4 days. The number ofviable cells in each well was then measured with CellTiter-Glo®Luminescent Cell Viability Assay (Promega) to calculate theconcentration of each test compound for 50% inhibition of cellproliferation (Sphere IC₅₀ value; μmol/L).

The experiment of Test Example 1 was performed for the compounds of eachExample. The concentrations of each test compound for 50% inhibition ofcell profeliration (Sphere IC₅₀ value; μmol/L) are shown in thefollowing Table.

Example IC₅₀ (μmol/L) 1 0.08 2 0.66 3 0.06 4 0.66 5 0.07 6 0.06 7 0.39 80.09 9 0.07 10 0.04 11 0.05 12 0.07 13 0.03 14 0.43 15 0.36 16 5.85 170.62 18 0.67 20 65.15 21 6.20 22 0.20 23 4.94 24 0.52 25 0.06 26 0.08 270.69 30 6.16 32 72.29 33 1.48 35 0.08 36 6.32 37 0.09 38 0.07 39 0.91 400.08 41 0.01 43 0.72 44 0.78 45 0.82 46 0.75 47 0.08 48 0.08 49 0.07 500.05 51 0.06 52 0.06 53 0.06 54 <0.01 55 0.08 56 0.07 58 0.18 59 0.61 600.25 61 0.37 62 0.71 63 3.59 64 0.09 65 0.08 66 0.70 68 0.56 69 0.76 700.04 71 0.92 72 3.45 73 0.61 74 0.49 75 0.40 76 0.68 77 0.62 78 0.56 790.55 80 0.62 81 0.95 82 3.79 83 0.72 84 6.78 85 0.61 86 0.47 87 0.60 885.03 89 0.07 90 0.07 91 0.07 92 0.07 93 <0.01 94 6.99 95 0.08 96 0.06 970.07 98 0.50 99 0.06 100 0.06 101 0.07 102 0.06 103 4.18 104 0.62 1055.90 108 6.63 109 7.07 110 0.68 111 0.69 112 0.71 113 0.76 115 0.57 1165.99 117 6.81 119 0.73 120 0.08 121 0.08

Test Example 2 Test for Inhibiting Sphere-Forming Ability of CancerCells (in the Presence of BSA)

HCT-116 cells were available from the American Type Culture Collection(ATCC). HCT-116 cells were cultured at 37° C. and 5% CO₂ using theMcCoy's 5a medium containing 10% fetal bovine serum (FBS) and 1%penicillin/streptomycin. HCT-116 cells were seeded in a 384 Well BlackClear Bottom Ultra-Low Attachment Microplate (Corning Cat. No.3827) inan amount of 350-800 cells/well using the DMEM/F12 medium containing 2%B27 supplement (GIBCO), 20 ng/mL epidermal growth factor (EGF)(peprotech), 10 ng/mL basic fibroblast growth factor (bFGF) (peprotech),5 μg/mL insulin (Sigma), 5% bovine serum albumin (BSA), and 1%penicillin/streptomycin. The test compounds were added into each well toadjust the final concentration of DMSO to 0.1%, and the cells werecultured for 4 days. The number of viable cells in each well was thenmeasured with CellTiter-Glo® Luminescent Cell Viability Assay (Promega)to calculate the concentration of each test compound for 50% inhibitionof cell proliferation (Sphere IC₅₀ value; μmol/L).

The experiment of Test Example 2 was performed for the compounds of eachExample. The concentrations of each test compound for 50% inhibition ofcell profeliration (Sphere IC₅₀ value; μmol/L) are shown in thefollowing Table.

Example IC₅₀ (μmol/L) 1 0.17 2 0.49 3 0.03 4 0.56 5 0.06 6 0.05 7 0.61 80.44 9 0.50 10 0.05 11 0.05 12 0.06 13 0.06 14 0.46 15 0.55 16 6.00 170.72 18 0.70 21 6.19 22 0.58 24 0.67 25 0.09 26 0.10 27 6.01 35 0.05 370.59 38 0.09 39 0.79 40 0.07 41 0.02 43 0.54 44 0.58 45 0.66 46 0.44 470.05 48 0.06 49 0.07 50 0.66 51 0.05 52 0.06 53 0.06 54 0.03 55 0.05 560.16 58 0.08 59 0.37 60 0.10 61 0.06 62 0.59 63 0.71 64 0.17 65 0.38 665.49 67 8.52 68 0.65 69 0.68 70 0.06 71 0.77 72 5.46 73 0.54 74 0.49 750.61 76 0.59 77 0.60 78 0.56 79 0.49 80 0.60 81 6.22 82 4.90 83 0.54 850.59 86 0.56 87 0.58 88 0.95 89 0.64 90 0.10 91 0.08 92 0.09 93 0.07 946.11 95 0.09 96 0.20 97 0.59 98 0.51 99 0.06 100 0.07 101 0.06 102 0.06103 6.10 104 0.53 105 5.12 107 6.34 110 0.58 111 0.98 112 6.34 113 0.58115 0.54 116 1.97 117 5.68 118 6.18 119 0.63 120 0.07 121 0.07

Test Example 3 Pharmacokinetic Assay in Mouse

A 7-week-old mouse (BALB/cAnNCrlCrlj, female, CHARLES RIVER LABORATORIESJAPAN, INC.) receives single oral administration of each compoundsuspended in 0.5% methylcellulose solution in a dose of 10 mg/kg or 100mg/kg. Blood is collected from the mouse 0.5, 1, 2, 4, 8 and 24 hoursafter the administration, and plasma from the blood is collected bycentrifugation. The area under the plasma concentration-time curve (AUC)is calculated on the basis of the concentration changes to calculate thebioavailability of each compound according to the following formula:

Bioavailabity (%)=AUC after oral administration/AUC after intravenousadministration×100

Plasma is deproteinized by adding methanol at the final concentration of80%, centrifuging the methanol solution, and filtrating the contrifugedsolution, and then the present compound in the deproteinized plasma isdetected and quantified with an LC-MS/MS (API4000, AB SCIEX). When thepresent compound is quantified, a calibration curve is prepared based onthe mouse plasma added with a given amount of the compound. Bezafibrateis used as internal standard.

Test Example 4 Anti-Tumor Effect to HCT-116 Tumor-Bearing Mouse

The present compound can be used to evaluate the anti-tumor effectthereof A 4 to 7-week-old nude mouse (BALB/cAnNCrj-nu/nu, female,CHARLES RIVER LABORATORIES JAPAN, INC.) received intradermaltransplantation of HCT-116 cells (ATCC) in an amount of 3×10⁶cells/mouse around the ventral portion. The engraftment of HCT-116 cellswas observed 5 to 14 days after the transplantation, and then eachcompound suspended in a solvent such as 0.5% methylcellulose solutionwas orally administrated to the mouse in a dose of 1 to 100 mg/kg one totwice daily. The tumor volume was measured over time after theadministration to evaluate the effect for reducing the tumor volume bythe administration of each compound. The tumor volume can be calculatedfrom the minor axis and the major axis of the tumor measured with adigital caliper (Mitutoyo) according to the following formula:

Tumor volume [mm³]=0.5×minor axis [mm]×(major axis [mm])²

The tumor volume in control administration group treated with only asolvent such as 0.5% methylcellulose solution was compared with that ofthe present compound administration group, and T/C value was calculatedaccording the following formula to evaluate the anti-tumor effect of thepresent compound.

T/C(%)=(the tumor volume at the end of administration in the presentcompound administration group−the tumor volume at the start ofadministration in the present compound administration group)/(the tumorvolume at the end of administration in the control administrationgroup−the tumor volume at the start of administration in the the controladministration group)×100

The T/C values (%) of the present compound on each dosage andadministration period in the HCT-116 tumor-bearing mouse are shownbelow.

administration Examples dosage (mg/kg) period (day) T/C (%) 3 10 17 90 330 17 79 5 30 17 71 5 100 17 42 6 30 17 73 10 30 17 55 10 100 17 49 1130 17 62 11 100 17 46 12 30 17 79 12 100 17 73 13 30 17 62 13 100 17 59

INDUSTRIAL APPLICABILITY

The present compound has a potent inhibitory effect on sphere-formingability of cancer cells, and is useful as an orally-availableanti-cancer agent.

1. A compound of formula (1):

or a pharmaceutically acceptable salt thereof, wherein ring Q¹ isoptionally-substituted C₆₋₁₀ aryl group, optionally-substituted C₃₋₁₀cycloalkyl group, or optionally-substituted 5- to 10-membered heteroarylgroup; R¹ and R² are independently hydrogen atom, halogen atom, or C₁₋₆alkyl group which may be optionally substituted with the same ordifferent 1 to 3 halogen atoms; W¹ is optionally-substituted C₁₋₄alkylene group; W²-Cy¹ is —NR^(3a)C(O)-Cy¹, —NR^(3a)C(O)O-Cy¹,—NR^(3a)C(O)OCH₂-Cy¹, —NR^(3a)C(O)NR^(3b)-Cy¹,—NR^(3a)C(O)NR^(3b)CH₂-Cy¹, —NR^(3a)C(O)CH₂O-Cy¹, —NR^(3a)C(O)CH₂-Cy¹,—NR^(3a)C(O)CH₂CH₂-Cy¹, —C(O)NR^(3a)-Cy¹, —C(O)NR^(3a)CH₂-Cy¹,—C(O)NR^(3a)CH₂CH₂-Cy¹, or —NR^(3a)C(O)—CR^(3c)═CR^(3d)-Cy¹ whereinR^(3a) and R^(3b) are independently hydrogen atom or C₁₋₆ alkyl group,and R^(3c) and R^(3d) are independently hydrogen atom, fluorine atom, orC₁₋₆ alkyl group; and Cy¹ is a group of the following formula (11),(12), (13), (15), or (16):

wherein ring Q² is optionally-substituted benzene ring,optionally-substituted pyridine ring, optionally-substituted pyrimidinering, optionally-substituted pyridazine ring, or optionally-substitutedpyrazine ring; ring Q³ is optionally-substituted 5-membered heteroarylring; n and m are independently 0, 1 or 2, provided that n and m are notsimultaneously 0; X and Z are independently NR⁵, —NR^(3e)C(O)—,—C(O)NR^(3e)—, or O wherein R⁵ is hydrogen atom, C₁₋₆ alkyl group whichmay be optionally substituted with the same or different 1 to 3 halogenatoms, or C₁₋₆ alkylcarbonyl; and R^(3e) is hydrogen atom or C₁₋₆ alkylgroup; p is 1, 2, 3, 4 or 5 ; and R⁴ is, independently when two or moreexist, hydrogen atom, halogen atom, hydroxy, oxo, C₁₋₆ alkyl group whichmay be optionally substituted with the same or different 1 to 3 halogenatoms, or C₁₋₆ alkoxy group which may be optionally substituted with thesame or different 1 to 3 halogen atoms; or when two R⁴ are attached tothe same carbon atom or adjacent carbon atoms on the ring, they may becombined with the carbon atom(s) to form (1) 5- to 8-membered saturatedor partially-unsaturated carbocyclic ring which may be optionallysubstituted with the same or different 1 to 4 groups selected from thegroup consisting of halogen atom, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy,or (2) 5- to 8-membered saturated or partially-unsaturated heterocyclicring which may be optionally substituted with the same or different 1 to4 groups selected from the group consisting of halogen atom, hydroxy,C₁₋₆ alkyl, and C₁₋₆ alkoxy.
 2. A compound of formula (1):

or a pharmaceutically acceptable salt thereof, wherein ring Q¹ isoptionally-substituted C₆₋₁₀ aryl group, optionally-substituted C₃₋₁₀cycloalkyl group, or optionally-substituted 5- to 10-membered heteroarylgroup; R¹ and R² are independently hydrogen atom, halogen atom, or C₁₋₆alkyl group which may be optionally substituted with the same ordifferent 1 to 3 halogen atoms; W¹ is optionally-substituted C₁₋₄alkylene group; W²-Cy¹ is —NR^(3a)C(O)-Cy¹, —NR^(3a)C(O)O-Cy¹,—NR^(3a)C(O)OCH₂-Cy¹, —NR^(3a)C(O)NR^(3b)-Cy¹,—NR^(3a)C(O)NR^(3b)CH₂-Cy¹, —NR^(3a)C(O)CH₂O-Cy¹, —NR^(3a)C(O)CH₂-Cy¹,—NR^(3a)C(O)CH₂CH₂-Cy¹, —C(O)NR^(3a)-Cy¹, —C(O)NR^(3a)CH₂-Cy¹, or—C(O)NR^(3a)CH₂CH₂-Cy¹ wherein R^(3a) and R^(3b) are independentlyhydrogen atom or C₁₋₆ alkyl group; and Cy¹ is a group of the followingformula (11), (12), or (13):

wherein ring Q² is optionally-substituted benzene ring,optionally-substituted pyridine ring, optionally-substituted pyrimidinering, optionally-substituted pyridazine ring, or optionally-substitutedpyrazine ring; ring Q³ is optionally-substituted 5-membered heteroarylring; n and m are independently 0, 1 or 2, provided that n and m are notsimultaneously 0; X is NR^(S) or O wherein R⁵ is hydrogen atom or C₁₋₆alkyl group which may be optionally substituted with the same ordifferent 1 to 3 halogen atoms; p is 1, 2, 3, 4 or 5; and R⁴ is,independently when two or more exist, hydrogen atom, halogen atom, orC₁₋₆ alkyl group which may be optionally substituted with the same ordifferent 1 to 3 halogen atoms.
 3. The compound according to claim 1 ora pharmaceutically acceptable salt thereof, wherein ring Q¹ is (1) C₆₋₁₀aryl group which may be optionally substituted with the same ordifferent 1 to 5 groups selected from the group consisting of: (a)halogen atom, (b) C₁₋₆ alkyl which may be optionally substituted withthe same or different 1 to 3 groups selected from the group consistingof halogen atom, hydroxy, and C₁₋₆ alkoxy, (c) C₁₋₆ alkoxy which may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (d)cyano, (e) C₆₋₁₀ aryl which may be optionally substituted with the sameor different 1 to 4 groups selected from the group consisting of halogenatom, C₁₋₆ alkyl, and C₁₋₆ alkoxy, (f) 5- or 6-membered heteroaryl whichmay be optionally substituted with the same or different 1 to 4 groupsselected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆alkoxy, (g) C₆₋₁₀ aryloxy which may be optionally substituted with thesame or different 1 to 4 groups selected from the group consisting ofhalogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy, (h) hydroxy, (i) amino whichmay be optionally substituted with the same or different 1 to 2 C₁₋₆alkyl groups, (j) aminocarbonyl wherein the amino moiety thereof may beoptionally substituted with the same or different 1 to 2 C₁₋₆ alkylgroups, (k) C₁₋₆ alkoxy-carbonyl wherein the alkoxy moiety thereof maybe optionally substituted with the same or different 1 to 3 groupsselected from the group consisting of halogen atom, hydroxy, and C₁₋₆alkoxy, (l) C₁₋₆ alkyl-carbonyl wherein the alkyl moiety thereof may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (m)C₁₋₆ alkylsulfonyl wherein the alkyl moiety thereof may be optionallysubstituted with the same or different 1 to 3 groups selected from thegroup consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (n) C₁₋₆alkyl-carbonylamino wherein the alkyl moiety thereof may be optionallysubstituted with the same or different 1 to 3 groups selected from thegroup consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (o) C₁₋₆alkylsulfonylamino wherein the alkyl moiety thereof may be optionallysubstituted with the same or different 1 to 3 groups selected from thegroup consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (p) C₁₋₆alkoxy-carbonylamino wherein the alkoxy moiety thereof may be optionallysubstituted with the same or different 1 to 3 groups selected from thegroup consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (q) C₁₋₆alkyl-carbonyloxy wherein the alkyl moiety thereof may be optionallysubstituted with the same or different 1 to 3 groups selected from thegroup consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (r)aminosulfonyl wherein the amino moiety thereof may be optionallysubstituted with the same or different 1 to 2 C₁₋₆ alkyl groups, and (s)C₃₋₁₀ cycloalkyl which may be optionally substituted with the same ordifferent 1 to 4 groups selected from the group consisting of halogenatom, hydroxy, and C₁₋₆ alkoxy, (2) C₃₋₁₀ cycloalkyl group which may beoptionally substituted with the same or different 1 to 5 groups selectedfrom the group consisting of (a) to (s) defined in the above (1), or (3)5- to 10-membered heteroaryl group which may be optionally substitutedwith the same or different 1 to 5 groups selected from the groupconsisting of (a) to (s) defined in the above (1); W¹ is C₁₋₄ alkylenegroup which may be optionally substituted with the same or different 1to 4 groups selected from the group consisting of halogen atom, hydroxy,and C₁₋₆ alkoxy; ring Q² is benzene ring, pyridine ring, pyrimidinering, pyridazine ring, or pyrazine ring wherein the benzene ring,pyridine ring, pyrimidine ring, pyridazine ring, and pyrazine ring maybe optionally substituted with the same or different 1 to 3 groupsselected from the group consisting of (1) halogen atom, (2) C₁₋₆ alkylwhich may be optionally substituted with the same or different 1 to 4groups selected from the group consisting of the same or different 1 to3 halogen atoms, hydroxy and C₁₋₆ alkoxy, (3) C₁₋₆ alkoxy which may beoptionally substituted with the same or different 1 to 3 halogen atoms,(4) hydroxyl, and (5) cyano; ring Q³ is 5-membered heteroaryl ring whichmay be optionally substituted with halogen atom or C₁₋₆ alkyl which maybe optionally substituted with the same or different 1 to 4 groupsselected from the group consisting of the same or different 1 to 3halogen atoms, hydroxy and C₁₋₆ alkoxy.
 4. The compound according toclaim 3 or a pharmaceutically acceptable salt thereof, wherein ring Q¹is (1) phenyl group which may be optionally substituted with the same ordifferent 1 to 5 groups selected from the group consisting of: (a)halogen atom, (b) C₁₋₆ alkyl which may be optionally substituted withthe same or different 1 to 3 groups selected from the group consistingof halogen atom, hydroxy and C₁₋₆ alkoxy, (c) C₁₋₆ alkoxy which may beoptionally substituted with the same or different 1 to 3 groups selectedfrom the group consisting of halogen atom, hydroxy and C₁₋₆ alkoxy, (d)cyano, (e) phenyl which may be optionally substituted with the same ordifferent 1 to 4 groups selected from the group consisting of halogenatom, C₁₋₆ alkyl and C₁₋₆ alkoxy, (f) 5- or 6-membered heteroaryl whichmay be optionally substituted with the same or different 1 to 4 groupsselected from the group consisting of halogen atom, C₁₋₆ alkyl and C₁₋₆alkoxy, and (g) phenoxy which may be optionally substituted with 1 to 4groups selected from the group consisting of halogen atom, C₁₋₆ alkyland C₁₋₆ alkoxy, (2) C₃₋₇ cycloalkyl group which may be optionallysubstituted with 1 to 4 groups selected from the group consisting of (a)to (g) defined in the above (1), or (3) pyridyl group which may beoptionally substituted with 1 to 4 groups selected from the groupconsisting of (a) to (g) defined in the above (1).
 5. The compoundaccording to claim 4 or a pharmaceutically acceptable salt thereof,wherein ring Q¹ is phenyl group which may be optionally substituted withthe same or different 1 to 5 groups selected from the group consistingof: (a) halogen atom, (b) C₁₋₆ alkyl which may be optionally substitutedwith the same or different 1 to 3 halogen atoms, and (c) C₁₋₆ alkoxywhich may be optionally substituted with the same or different 1 to 3halogen atoms.
 6. The compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein W¹ is methylene groupwhich may be optionally substituted with the same or different 1 to 2halogen atoms or ethylene group which may be optionally substituted withthe same or different 1 to 4 halogen atoms.
 7. The compound according toclaim 1 or a pharmaceutically acceptable salt thereof, wherein W²-Cy¹ is—NR^(3a)C(O)-Cy¹ or —C(O)NR^(3a)-Cy¹ wherein R^(3a) is hydrogen atom orC₁₋₆ alkyl group.
 8. The compound according to claim 7 or apharmaceutically acceptable salt thereof, wherein W²-Cy¹ is—NR^(3a)C(O)-Cy¹ wherein R^(3a) is hydrogen atom or C₁₋₆ alkyl group. 9.The compound according to claim 1 represented by formula (1a):

or a pharmaceutically acceptable salt thereof, wherein ring Q^(1a) isphenyl group, pyridyl group, or cyclohexyl group; q is 1, 2, 3, 4 or 5;R¹¹ is, independently when two or more exist, (1) hydrogen atom, (2)halogen atom, (3) C₁₋₆ alkyl group which may be optionally substitutedwith the same or different 1 to 3 halogen atoms, or (4) C₁₋₆ alkoxygroup which may be optionally substituted with the same or different 1to 3 halogen atoms; R¹ and R² are independently hydrogen atom, halogenatom, or C₁₋₆ alkyl group which may be optionally substituted with thesame or different 1 to 3 halogen atoms; W^(1a) is methylene group whichmay be optionally substituted with the same or different 1 to 2 halogenatoms or ethylene group which may be optionally substituted with thesame or different 1 to 4 halogen atoms; W^(2a)-Cy² is —NR^(3a)C(O)-Cy²or —C(O)NR^(3a)-Cy² wherein R^(3a) is hydrogen atom or C₁₋₆ alkyl group;and Cy² is a group of the following formula (21), (22), or (23):

wherein X¹ is N or CR¹²; X² is N or CR¹³; X³ is N or CR¹⁴; X⁴ is N orCR¹⁵; X⁵ is S, 0 or NH; provided that X¹, X² and X³ are notsimultaneously N; R¹², R¹³, R¹⁴ and R¹⁵ are independently (1) hydrogenatom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionallysubstituted with the same or different 1 to 3 halogen atoms, or (4) C₁₋₆alkoxy group which may be optionally substituted with the same ordifferent 1 to 3 halogen atoms; n and m are independently 0, 1 or 2,provided that n and m are not simultaneously 0; p is 1, 2, 3, 4 or 5;and R⁴ is, independently when two or more exist, hydrogen atom, halogenatom, or C₁₋₆ alkyl group which may be optionally substituted with thesame or different 1 to 3 halogen atoms.
 10. The compound according toclaim 9 or a pharmaceutically acceptable salt thereof, wherein ringQ^(1a) is phenyl group.
 11. The compound according to claim 9 or apharmaceutically acceptable salt thereof, wherein W^(2a)-Cy² is—NHC(O)-Cy².
 12. The compound according to claim 9 or a pharmaceuticallyacceptable salt thereof, wherein W^(2a)-Cy² is —C(O)NH-Cy².
 13. Thecompound according to claim 9 or a pharmaceutically acceptable saltthereof, wherein Cy² is a group of formula (21) or (23).
 14. Thecompound according to claim 9 or a pharmaceutically acceptable saltthereof, wherein Cy² is a group of formula (22); X⁴ is N or CH; and X⁵is S.
 15. The compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are hydrogen atom.
 16. Thecompound according to claim 1 represented by formula (1b):

or a pharmaceutically acceptable salt thereof, wherein X¹ is N or CR¹²;X² is N or CR¹³; X³ is N or CR¹⁴; provided that X¹, X² and X³ are notsimultaneously N; W^(2b) is —NHC(O)—, or —C(O)NH—; R¹², R¹³, R¹⁴, R²¹,R²², R²³, R²⁴, and R²⁵ are independently (1) hydrogen atom, (2) halogenatom, (3) C₁₋₆ alkyl group which may be optionally substituted with thesame or different 1 to 3 halogen atoms, or (4) C₁₋₆ alkoxy group whichmay be optionally substituted with the same or different 1 to 3 halogenatoms; n and m are independently 0, 1 or 2, provided that n and m arenot simultaneously 0; p is 1, 2, 3, 4 or 5; and R⁴ is, independentlywhen two or more exist, hydrogen atom, halogen atom, or C₁₋₆ alkyl groupwhich may be optionally substituted with the same or different 1 to 3halogen atoms.
 17. The compound according to claim 16 or apharmaceutically acceptable salt thereof, wherein R²² is halogen atom orC₁₋₆ alkyl group which may be optionally substituted with the same ordifferent 1 to 3 halogen atoms.
 18. The compound according to claim 16or a pharmaceutically acceptable salt thereof, wherein R²² is halogenatom.
 19. The compound according to claim 16 or a pharmaceuticallyacceptable salt thereof, wherein R²¹, R²³, R²⁴ and R²⁵ are independently(1) hydrogen atom, (2) halogen atom, or (3) C₁₋₆ alkyl group which maybe optionally substituted with the same or different 1 to 3 halogenatoms.
 20. The compound according to claim 16 or a pharmaceuticallyacceptable salt thereof, wherein W^(2b) is —NHC(O)—.
 21. The compoundaccording to claim 16 or a pharmaceutically acceptable salt thereof,wherein W^(2b) is —C(O)NH—.
 22. The compound according to claim 9 or apharmaceutically acceptable salt thereof, wherein only one of X¹, X² andX³ is N.
 23. The compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is hydrogen atom.
 24. The compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof,wherein n is 1 and m is 1; or n is 2 and m is
 0. 25. The compoundaccording to claim 24 or a pharmaceutically acceptable salt thereof,wherein n is 1 and m is
 1. 26. The compound according to claim 1selected from the following compounds or a pharmaceutically acceptablesalt thereof:N-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamide,N-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamide,N-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamide,8-fluoro-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxamide,N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxamide,N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide,N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide,N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,1-(3,4-difluorobenzyl)-N-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-1H-imidazole-4-carboxamide,N-[1-(3,5-difluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-[1-(3,4-difluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-{1-[3-(trifluoromethoxy)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-[1-(3-phenoxybenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-[1-(4-chloro-3-fluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-[1-(3-chloro-5-fluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-{1-[4-fluoro-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-{1-[4-chloro-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-{1-[4-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-[1-(4-chlorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-{1-[3-chloro-5-(trifluoromethoxy)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,N-[1-(3-phenoxybenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-[1-(4-chloro-3-fluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-[1-(3-chloro-5-fluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-{1-[4-fluoro-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-{1-[4-chloro-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-[1-(3-chloro-4-fluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-{1-[4-methyl-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-{1-[3-fluoro-5-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-{1-[3-chloro-5-(trifluoromethoxy)benzyl]-1H-imidazol-4-yl}-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-[1-(3,5-dichlorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,andN-[1-(3,4-dichlorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide.27. The compound according to claim 1 selected from the followingcompounds or a pharmaceutically acceptable salt thereof:N-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamide,8-fluoro-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide,N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide,N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide,andN-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide.28-31. (canceled)
 32. A method for treating cancer which comprisesadministering a therapeutically effective amount of the compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof to apatient in need thereof.
 33. (canceled)
 34. A pharmaceutical compositionfor the treatment of cancer comprising the compound according to claim 1or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.
 35. (canceled)
 36. A compound selected from thefollowing compounds or a pharmaceutically acceptable salt thereof:


37. A method for treating tumor which comprises administering atherapeutically effective amount of the compound according to claim 1 ora pharmaceutically acceptable salt thereof to a patient in need thereof,wherein the tumor is acute leukemia, chronic lymphatic leukemia, chronicmyelocytic leukemia, polycythemia vera, malignant lymphoma, myeloma,brain tumor, head and neck cancer, esophageal cancer, thyroid cancer,small cell lung cancer, non-small cell lung cancer, breast cancer,stomach cancer, gallbladder or bile duct cancer, liver cancer,pancreatic cancer, colon cancer, rectal cancer, ovarian cancer,chorioepithelioma, endometrial cancer, cervical cancer, urothelialcancer, renal cell cancer, prostate cancer, testicular tumor, Wilms'tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma,or soft tissue sarcoma.
 38. A method for treating cancer which comprisesadministering a therapeutically effective amount of the compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof andanother anti-cancer agent selected from the group consisting of ananticancer alkylating agent, an anticancer antimetabolite, an anticancerantibiotic, a plant-based anti-cancer agent, an anticancer platinumcoordination compound, an anticancer camptothecin derivative, ananticancer tyrosine kinase inhibitor, a serine-threonine kinaseinhibitor, a phospholipid kinase inhibitor, a monoclonal antibody, aninterferon, a biological response modifier, a hormone preparation, animmune checkpoint inhibitor, an epigenetics-related molecule inhibitor,a post-translational protein modification inhibitor, and an anti-canceragent other than the foregoings or a pharmaceutically acceptable saltthereof to a patient in need thereof.
 39. A method for treating cancerwhich comprises administering a therapeutically effective amount of thecompound according to claim 26 or a pharmaceutically acceptable saltthereof to a patient in need thereof.
 40. A pharmaceutical compositioncomprising the compound according to claim 26 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient. 41.A method for treating tumor which comprises administering atherapeutically effective amount of the compound according to claim 26or a pharmaceutically acceptable salt thereof to a patient in needthereof, wherein the tumor is acute leukemia, chronic lymphaticleukemia, chronic myelocytic leukemia, polycythemia vera, malignantlymphoma, myeloma, brain tumor, head and neck cancer, esophageal cancer,thyroid cancer, small cell lung cancer, non-small cell lung cancer,breast cancer, stomach cancer, gallbladder or bile duct cancer, livercancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer,chorioepithelioma, endometrial cancer, cervical cancer, urothelialcancer, renal cell cancer, prostate cancer, testicular tumor, Wilms'tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma,or soft tissue sarcoma.
 42. A method for treating cancer which comprisesadministering a therapeutically effective amount of the compoundaccording to claim 26 or a pharmaceutically acceptable salt thereof andanother anti-cancer agent selected from the group consisting of ananticancer alkylating agent, an anticancer antimetabolite, an anticancerantibiotic, a plant-based anti-cancer agent, an anticancer platinumcoordination compound, an anticancer camptothecin derivative, ananticancer tyrosine kinase inhibitor, a serine-threonine kinaseinhibitor, a phospholipid kinase inhibitor, a monoclonal antibody, aninterferon, a biological response modifier, a hormone preparation, animmune checkpoint inhibitor, an epigenetics-related molecule inhibitor,a post-translational protein modification inhibitor, and an anti-canceragent other than the foregoings or a pharmaceutically acceptable saltthereof to a patient in need thereof.